RESUMEN
The coronavirus disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been spread worldwide for more than 3 years. Although the hospitalization rate and mortality have decreased dramatically due to wide vaccination effort and improved treatment options, the disease is still a global health issue due to constant viral mutations, causing negative impact on social and economic activities. In addition, long COVID and complications arising from COVID-19 weeks after infection have become a concern for public health experts. Therefore, better treatments for COVID-19 are still needed. Herein, we describe a class of macrocyclic peptidomimetic compounds that are potent inhibitors of SARS-Cov-2 3CL protease (3CLpro). Significantly, some of the compounds showed a higher stability against human liver microsomes (HLM t1/2 > 180 min) and may be suitable for oral administration without the need for a pharmacokinetic (PK) boosting agent such as ritonavir.
Asunto(s)
Antivirales , Proteasas 3C de Coronavirus , Compuestos Macrocíclicos , SARS-CoV-2 , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Proteasas 3C de Coronavirus/metabolismo , Humanos , SARS-CoV-2/efectos de los fármacos , Compuestos Macrocíclicos/química , Compuestos Macrocíclicos/farmacología , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/farmacocinética , Antivirales/farmacología , Antivirales/química , Antivirales/síntesis química , Antivirales/farmacocinética , Microsomas Hepáticos/metabolismo , Peptidomiméticos/farmacología , Peptidomiméticos/química , Peptidomiméticos/síntesis química , Descubrimiento de Drogas , Tratamiento Farmacológico de COVID-19 , Inhibidores de Proteasas/farmacología , Inhibidores de Proteasas/química , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacocinética , Relación Estructura-ActividadRESUMEN
The development of theranostic radiotracers relies on their binding to specific molecular markers of a particular disease and the use of corresponding radiopharmaceutical pairs thereafter. This study reports the use of multiamine macrocyclic moieties (MAs), as linkers or chelators, in tracers targeting the neurotensin receptor-1 (NTSR-1). The goal is to achieve elevated tumor uptake, minimal background interference, and prolonged tumor retention in NTSR-1-positive tumors. Methods: We synthesized a series of neurotensin antagonists bearing MA linkers and metal chelators. The MA unit is hypothesized to establish a strong interaction with the cell membrane, and the addition of a second chelator may enhance water solubility, consequently reducing liver uptake. Small-animal PET/CT imaging of [64Cu]Cu-DOTA-SR-3MA, [64Cu]Cu-NT-CB-NOTA, [68Ga]Ga-NT-CB-NOTA, [64Cu]Cu-NT-CB-DOTA, and [64Cu]Cu-NT-Sarcage was acquired at 1, 4, 24, and 48 h after injection using H1299 tumor models. [55Co]Co-NT-CB-NOTA was also tested in HT29 (high NTSR-1 expression) and Caco2 (low NTSR-1 expression) colorectal adenocarcinoma tumor models. Saturation binding assay and internalization of [55Co]Co-NT-CB-NOTA were used to test tracer specificity and internalization in HT29 cells. Results: In vivo PET imaging with [64Cu]Cu-NT-CB-NOTA, [68Ga]Ga-NT-CB-NOTA, and [55Co]Co-NT-CB-NOTA revealed high tumor uptake, high tumor-to-background contrast, and sustained tumor retention (≤48 h after injection) in NTSR-1-positive tumors. Tumor uptake of [64Cu]Cu-NT-CB-NOTA remained at 76.9% at 48 h after injection compared with uptake 1 h after injection in H1299 tumor models, and [55Co]Co-NT-CB-NOTA was retained at 60.2% at 24 h compared with uptake 1 h after injection in HT29 tumor models. [64Cu]Cu-NT-Sarcage also showed high tumor uptake with low background and high tumor retention 48 h after injection Conclusion: Tumor uptake and pharmacokinetic properties of NTSR-1-targeting radiopharmaceuticals were greatly improved when attached with different nitrogen-containing macrocyclic moieties. The study results suggest that NT-CB-NOTA labeled with either 64Cu/67Cu, 55Co/58mCo, or 68Ga (effect of 177Lu in tumor to be determined in future studies) and NT-Sarcage labeled with 64Cu/67Cu or 55Co/58mCo may be excellent diagnostic and therapeutic radiopharmaceuticals targeting NTSR-1-positive cancers. Also, the introduction of MA units to other ligands is warranted in future studies to test the generality of this approach.
Asunto(s)
Radioisótopos de Cobre , Radioisótopos de Galio , Compuestos Macrocíclicos , Radiofármacos , Receptores de Neurotensina , Receptores de Neurotensina/metabolismo , Receptores de Neurotensina/antagonistas & inhibidores , Animales , Ratones , Radiofármacos/farmacocinética , Radiofármacos/química , Distribución Tisular , Humanos , Compuestos Macrocíclicos/química , Compuestos Macrocíclicos/farmacocinética , Marcaje Isotópico , Línea Celular Tumoral , Aminas/química , Medicina de Precisión , Radioquímica , Técnicas de Química Sintética , Tomografía Computarizada por Tomografía de Emisión de PositronesRESUMEN
We report the [natMn/52Mn]Mn(II) complexes of the macrocyclic chelators PYAN [3,6,10,13-tetraaza-1,8(2,6)-dipyridinacyclotetradecaphane] and CHXPYAN [(41R,42R,101R,102R)-3,5,9,11-tetraaza-1,7(2,6)-dipyridina-4,10(1,2)-dicyclohexanacyclododecaphane]. The X-ray crystal structures of Mn-PYAN and Mn-CHXPYAN evidence distorted octahedral geometries through coordination of the nitrogen atoms of the macrocycles. Cyclic voltammetry studies evidence reversible processes due to the Mn(II)/Mn(III) pair, indicating that the complexes are resistant to oxidation. CHXPYAN forms a more thermodynamically stable and kinetically inert Mn(II) complex than PYAN. Radiochemical studies with the radioactive isotope manganese-52 (52Mn, t1/2 = 5.6 days) evidenced better radiochemical yields for CHXPYAN than for PYAN. Both [52Mn]Mn(II) complexes remained stable in mouse and human serum, so in vivo stability studies were carried out. Positron emission tomography/computed tomography scans and biodistribution assays indicated that [52Mn]Mn-PYAN has a distribution pattern similar to that of [52Mn]MnCl2, showing persistent radioactivity accumulation in the kidneys. Conversely, [52Mn]Mn-CHXPYAN remained stable in vivo, clearing quickly from the liver and kidneys.
Asunto(s)
Quelantes , Compuestos Macrocíclicos , Manganeso , Tomografía de Emisión de Positrones , Animales , Ratones , Tomografía de Emisión de Positrones/métodos , Compuestos Macrocíclicos/química , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/farmacocinética , Manganeso/química , Quelantes/química , Quelantes/síntesis química , Cristalografía por Rayos X , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Complejos de Coordinación/farmacocinética , Distribución Tisular , Modelos Moleculares , Radiofármacos/química , Radiofármacos/síntesis química , Radiofármacos/farmacocinética , Estabilidad de MedicamentosRESUMEN
The elevated activity of leucine-rich repeat kinase 2 (LRRK2) is implicated in the pathogenesis of Parkinson's disease (PD). The quest for effective LRRK2 inhibitors has been impeded by the formidable challenge of crossing the blood-brain barrier (BBB). We leveraged structure-based de novo design and developed robust three-dimensional quantitative structure-activity relationship (3D-QSAR) models to predict BBB permeability, enhancing the likelihood of the inhibitor's brain accessibility. Our strategy involved the synthesis of macrocyclic molecules by linking the two terminal nitrogen atoms of HG-10-102-01 with an alkyl chain ranging from 2 to 4 units, laying the groundwork for innovative LRRK2 inhibitor designs. Through meticulous computational and synthetic optimization of both biochemical efficacy and BBB permeability, 9 out of 14 synthesized candidates demonstrated potent low-nanomolar inhibition and significant BBB penetration. Further assessments of in vitro and in vivo effectiveness, coupled with pharmacological profiling, highlighted 8 as the promising new lead compound for PD therapeutics.
Asunto(s)
Barrera Hematoencefálica , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Enfermedad de Parkinson , Inhibidores de Proteínas Quinasas , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/antagonistas & inhibidores , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/metabolismo , Barrera Hematoencefálica/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Animales , Humanos , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/uso terapéutico , Ratones , Relación Estructura-Actividad Cuantitativa , Permeabilidad , Compuestos Macrocíclicos/química , Compuestos Macrocíclicos/farmacología , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/farmacocinética , MasculinoRESUMEN
Previously, we demonstrated that linear peptide epoxyketones targeting the immunoproteasome (iP) could ameliorate cognitive deficits in mouse models of Alzheimer's disease (AD) independently of amyloid deposition. We also reported the first iP-targeting macrocyclic peptide epoxyketones, which exhibit improved metabolic stability compared with their linear counterparts. Here, we prepared additional macrocyclic peptide epoxyketones and compared them with existing macrocyclic iP inhibitors by assessing Caco2 cell-based permeability and microsomal stability, providing the four best macrocyclic iP inhibitors. We then evaluated the four compounds using the Ames test and the potency assays in BV2 cells, selecting compound 5 as our AD drug lead. When 5 was administered intravenously (40 mg/kg) or orally (150 mg/kg) into healthy BALB/c mice, we observed considerable iP inhibition in the mouse brain, indicating good blood-brain barrier permeability and target engagement. Combined results suggest that 5 is a promising AD drug lead that may need further investigation.
Asunto(s)
Enfermedad de Alzheimer , Barrera Hematoencefálica , Encéfalo , Ratones Endogámicos BALB C , Animales , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Humanos , Barrera Hematoencefálica/metabolismo , Ratones , Células CACO-2 , Encéfalo/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Permeabilidad , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacología , Péptidos Cíclicos/farmacocinética , Inhibidores de Proteasoma/farmacología , Inhibidores de Proteasoma/química , Compuestos Macrocíclicos/química , Compuestos Macrocíclicos/farmacología , Compuestos Macrocíclicos/farmacocinética , Cetonas/química , Cetonas/farmacología , Relación Estructura-ActividadRESUMEN
The supramolecular-based macrocyclic amphiphiles have fascinating attention and find extensive utilization in the pharmaceutical industry for efficient drug delivery. In this study, we designed and synthesized a new supramolecular amphiphilic macrocycle to serve as an efficient nanocarrier, achieved by treating 4-hydroxybenzaldehyde with 1-bromotetradecane. The derivatized product was subsequently treated with resorcinol to cyclize, resulting in the formation of a calix(4)-resorcinarene-based supramolecular amphiphilic macrocycle. The synthesized macrocycle and intermediate products were characterized using mass spectrometry, IR, and 1H NMR spectroscopic techniques. The amphotericin-B (Amph-B)-loaded and unloaded amphiphiles were screened for biocompatibility studies, vesicle formation, particle shape, size, surface charge, drug entrapment, in-vitro release profile, and stability through atomic force microscopy (AFM), Zetasizer, HPLC, and FT-IR. Amph-B -loaded macrocycle-based niosomal vesicles were investigated for in-vivo bioavailability in rabbits. The synthesized macrocycle exhibited no cytotoxicity against normal mouse fibroblast cells and was found to be hemocompatible and safe in mice following an acute toxicity study. The drug-loaded macrocycle-based vesicles appeared spherical, nano-sized, and homogeneous in size, with a notable negative surface charge. The vesicles remained stable after 30 days of storage. The results of Amph-B oral bioavailability and pharmacokinetics revealed that the newly tailored niosomal formulation enhanced drug solubility, protected drug degradation at gastric pH, facilitated sustained drug release at the specific target site, and delayed plasma drug clearance. Incorporating such advanced niosomal formulations in the field of drug delivery systems has the potential to revolutionize therapeutic outcomes and improve the quality of patient well-being.
Asunto(s)
Anfotericina B , Disponibilidad Biológica , Calixarenos , Portadores de Fármacos , Animales , Masculino , Ratones , Conejos , Administración Oral , Anfotericina B/farmacocinética , Anfotericina B/química , Anfotericina B/farmacología , Anfotericina B/administración & dosificación , Calixarenos/química , Portadores de Fármacos/química , Portadores de Fármacos/síntesis química , Liberación de Fármacos , Compuestos Macrocíclicos/química , Compuestos Macrocíclicos/farmacocinética , Compuestos Macrocíclicos/farmacología , Compuestos Macrocíclicos/síntesis química , Nanopartículas/química , Tamaño de la Partícula , Fenilalanina/química , Fenilalanina/análogos & derivados , Tensoactivos/química , Tensoactivos/síntesis química , FemeninoRESUMEN
The three pan-genotypic HCV NS3/4A protease inhibitors (PIs) currently in clinical use-grazoprevir, glecaprevir, and voxilaprevir-are quinoxaline-based P2-P4 macrocycles and thus exhibit similar resistance profiles. Using our quinoxaline-based P1-P3 macrocyclic lead compounds as an alternative chemical scaffold, we explored structure-activity relationships (SARs) at the P2 and P4 positions to develop pan-genotypic PIs that avoid drug resistance. A structure-guided strategy was used to design and synthesize two series of compounds with different P2 quinoxalines in combination with diverse P4 groups of varying sizes and shapes, with and without fluorine substitutions. Our SAR data and cocrystal structures revealed the interplay between the P2 and P4 groups, which influenced inhibitor binding and the overall resistance profile. Optimizing inhibitor interactions in the S4 pocket led to PIs with excellent antiviral activity against clinically relevant PI-resistant HCV variants and genotype 3, providing potential pan-genotypic inhibitors with improved resistance profiles.
Asunto(s)
Antivirales/uso terapéutico , Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Compuestos Macrocíclicos/uso terapéutico , Inhibidores de Proteasas/uso terapéutico , Quinoxalinas/uso terapéutico , Animales , Antivirales/síntesis química , Antivirales/metabolismo , Antivirales/farmacocinética , Cristalografía por Rayos X , Farmacorresistencia Viral/efectos de los fármacos , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/metabolismo , Compuestos Macrocíclicos/farmacocinética , Masculino , Estructura Molecular , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/metabolismo , Inhibidores de Proteasas/farmacocinética , Unión Proteica , Quinoxalinas/síntesis química , Quinoxalinas/metabolismo , Quinoxalinas/farmacocinética , Ratas Sprague-Dawley , Serina Proteasas/metabolismo , Relación Estructura-Actividad , Proteínas no Estructurales Virales/antagonistas & inhibidores , Proteínas no Estructurales Virales/metabolismoRESUMEN
The current opioid crisis highlights the urgent need to develop safe and effective pain medications. Thus, neurotensin (NT) compounds represent a promising approach, as the antinociceptive effects of NT are mediated by activation of the two G protein-coupled receptor subtypes (i.e., NTS1 and NTS2) and produce potent opioid-independent analgesia. Here, we describe the synthesis and pharmacodynamic and pharmacokinetic properties of the first constrained NTS2 macrocyclic NT(8-13) analog. The Tyr11 residue of NT(8-13) was replaced with a Trp residue to achieve NTS2 selectivity, and a rationally designed side-chain to side-chain macrocyclization reaction was applied between Lys8 and Trp11 to constrain the peptide in an active binding conformation and limit its recognition by proteolytic enzymes. The resulting macrocyclic peptide, CR-01-64, exhibited high-affinity for NTS2 (Ki 7.0 nM), with a more than 125-fold selectivity over NTS1, as well as an improved plasma stability profile (t1/2 > 24 h) compared with NT (t1/2 ~ 2 min). Following intrathecal administration, CR-01-64 exerted dose-dependent and long-lasting analgesic effects in acute (ED50 = 4.6 µg/kg) and tonic (ED50 = 7.1 µg/kg) pain models as well as strong mechanical anti-allodynic effects in the CFA-induced chronic inflammatory pain model. Of particular importance, this constrained NTS2 analog exerted potent nonopioid antinociceptive effects and potentiated opioid-induced analgesia when combined with morphine. At high doses, CR-01-64 did not cause hypothermia or ileum relaxation, although it did induce mild and short-term hypotension, all of which are physiological effects associated with NTS1 activation. Overall, these results demonstrate the strong therapeutic potential of NTS2-selective analogs for the management of pain.
Asunto(s)
Analgésicos no Narcóticos/farmacología , Compuestos Macrocíclicos/farmacología , Receptores de Neurotensina/efectos de los fármacos , Analgésicos no Narcóticos/síntesis química , Analgésicos no Narcóticos/farmacocinética , Analgésicos Opioides/farmacología , Animales , Células CHO , Cricetinae , Cricetulus , Ciclización , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Sinergismo Farmacológico , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/etiología , Inflamación/complicaciones , Inflamación/tratamiento farmacológico , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/farmacocinética , Masculino , Morfina/farmacología , Dimensión del Dolor/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Especificidad por SustratoRESUMEN
Since 2011, with the approval of crizotinib and subsequent approval of four additional targeted therapies, anaplastic lymphoma kinase (ALK) inhibitors have become important treatments for a subset of patients with lung cancer. Each generation of ALK inhibitor showed improvements in terms of central nervous system (CNS) penetration and potency against wild-type (WT) ALK, yet a key continued limitation is their susceptibility to resistance from ALK active-site mutations. The solvent front mutation (G1202R) and gatekeeper mutation (L1196M) are major resistance mechanisms to the first two generations of inhibitors while patients treated with the third-generation ALK inhibitor lorlatinib often experience progressive disease with multiple mutations on the same allele (mutations in cis, compound mutations). TPX-0131 is a compact macrocyclic molecule designed to fit within the ATP-binding boundary to inhibit ALK fusion proteins. In cellular assays, TPX-0131 was more potent than all five approved ALK inhibitors against WT ALK and many types of ALK resistance mutations, e.g., G1202R, L1196M, and compound mutations. In biochemical assays, TPX-0131 potently inhibited (IC50 <10 nmol/L) WT ALK and 26 ALK mutants (single and compound mutations). TPX-0131, but not lorlatinib, caused complete tumor regression in ALK (G1202R) and ALK compound mutation-dependent xenograft models. Following repeat oral administration of TPX-0131 to rats, brain levels of TPX-0131 were approximately 66% of those observed in plasma. Taken together, preclinical studies show that TPX-0131 is a CNS-penetrant, next-generation ALK inhibitor that has potency against WT ALK and a spectrum of acquired resistance mutations, especially the G1202R solvent front mutation and compound mutations, for which there are currently no effective therapies.
Asunto(s)
Quinasa de Linfoma Anaplásico , Antineoplásicos , Transformación Celular Neoplásica , Resistencia a Antineoplásicos , Compuestos Macrocíclicos , Mutación , Inhibidores de Proteínas Quinasas , Animales , Femenino , Humanos , Ratones , Quinasa de Linfoma Anaplásico/antagonistas & inhibidores , Quinasa de Linfoma Anaplásico/genética , Quinasa de Linfoma Anaplásico/metabolismo , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Apoptosis , Linfocitos B/efectos de los fármacos , Proliferación Celular , Transformación Celular Neoplásica/efectos de los fármacos , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Compuestos Macrocíclicos/química , Compuestos Macrocíclicos/farmacocinética , Compuestos Macrocíclicos/farmacología , Ratones Desnudos , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/farmacología , Ratas Sprague-Dawley , Distribución Tisular , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Four high-spin Fe(III) macrocyclic complexes, including three dinuclear and one mononuclear complex, were prepared toward the development of more effective iron-based magnetic resonance imaging (MRI) contrast agents. All four complexes contain a 1,4,7-triazacyclononane macrocyclic backbone with two hydroxypropyl pendant groups, an ancillary aryl or biphenyl group, and a coordination site for a water ligand. The pH potentiometric titrations support one or two deprotonations of the complexes, most likely deprotonation of hydroxypropyl groups at near-neutral pH. Variable-temperature 17O NMR studies suggest that the inner-sphere water ligand is slow to exchange with bulk water on the NMR time scale. Water proton T1 relaxation times measured for solutions of the Fe(III) complexes at pH 7.2 showed that the dinuclear complexes have a 2- to 3-fold increase in r1 relaxivity in comparison to the mononuclear complex per molecule at field strengths ranging from 1.4 T to 9.4 T. The most effective agent, a dinuclear complex with macrocycles linked through para-substitution of an aryl group (Fe2(PARA)), has an r1 of 6.7 mM-1 s-1 at 37 °C and 4.7 T or 3.3 mM-1 s-1 per iron center in the presence of serum albumin and shows enhanced blood pool and kidney contrast in mice MRI studies.
Asunto(s)
Medios de Contraste/química , Complejos de Coordinación/química , Compuestos Férricos/química , Compuestos Macrocíclicos/química , Imagen por Resonancia Magnética , Animales , Medios de Contraste/síntesis química , Medios de Contraste/farmacocinética , Complejos de Coordinación/síntesis química , Complejos de Coordinación/farmacocinética , Compuestos Férricos/farmacocinética , Humanos , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/farmacocinética , Ratones , Ratones Endogámicos BALB C , Estructura Molecular , Albúmina Sérica Humana/químicaRESUMEN
Phosphonates-based agents are well-known bone-seeking radiopharmaceuticals with application in detection and therapy. With higher sensitivity and resolution offered by Positron Emission Tomography (PET), tracers based on this technique are gaining huge attention. 68Ga-based generator and radiotracers render independence from the on-site cyclotron. We report the development of 68Ga-labeled DOTA-based bismacrocyclic phosphonate derivative, for bone PET imaging. The synthesis and characterization of 68Ga- DO3P-AME-DO3P was carried out in > 95% purity. The radiotracer displayed high stability and low binding affinity (<3%) to blood serum. High in vitro binding affinity were observed for synthetic hydroxyapatite, SAOS-2, osteoclast and osteoblast cells. In vivo pharmacokinetics revealed fast washout with biphasic release pattern. The deposition of radiotracer in osseous tissues was high (Bone/Muscle ratio:18), as studied from the biodistribution studies. In vivo PET/CT and biodistribution analyses revealed the ability of 68Ga-DO3P-AME-DO3P to target and accumulate in bone, thus displaying its potential as a PET bone imaging agent.
Asunto(s)
Acetamidas/química , Huesos/diagnóstico por imagen , Compuestos Macrocíclicos/química , Compuestos Organofosforados/química , Tomografía de Emisión de Positrones , Radiofármacos/química , Acetamidas/sangre , Acetamidas/farmacocinética , Radioisótopos de Galio , Humanos , Compuestos Macrocíclicos/sangre , Compuestos Macrocíclicos/farmacocinética , Estructura Molecular , Compuestos Organofosforados/sangre , Compuestos Organofosforados/farmacocinética , Radiofármacos/sangre , Radiofármacos/farmacocinética , Distribución TisularRESUMEN
Complexes of Fe(III) that contain a triazacyclononane (TACN) macrocycle, two pendant hydroxyl groups, and a third ancillary pendant show promise as MRI contrast agents. The ancillary group plays an important role in tuning the solution relaxivity of the Fe(III) complex and leads to large changes in MRI contrast enhancement in mice. Two new Fe(III) complexes, one with a third coordinating hydroxypropyl pendant, Fe(L2), and one with an anionic non-coordinating sulfonate group, Fe(L1)(OH2), are compared. Both complexes have a deprotonated hydroxyl group at neutral pH and electrode potentials representative of a stabilized trivalent iron center. The r1 relaxivity of the Fe(L1)(OH2) complex is double that of the saturated complex, Fe(L2), at 4.7 T, 37 °C in buffered solutions. However, variable-temperature 17O-NMR experiments show that the inner-sphere water of Fe(L1)(OH2) does not exchange rapidly with bulk water under these conditions. The pendant sulfonate group in Fe(L1)(OH2) confers high solubility to the complex in comparison to Fe(L2) or previously studied analogues with benzyl groups. Dynamic MRI studies of the two complexes showed major differences in their pharmacokinetics clearance rates compared to an analogue containing a benzyl ancillary group. Rapid blood clearance and poor binding to serum albumin identify Fe(L1)(OH2) for development as an extracellular fluid contrast agent.
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Medios de Contraste , Compuestos Férricos , Compuestos Macrocíclicos , Imagen por Resonancia Magnética , Animales , Medios de Contraste/química , Medios de Contraste/farmacocinética , Medios de Contraste/farmacología , Compuestos Férricos/química , Compuestos Férricos/farmacocinética , Compuestos Férricos/farmacología , Compuestos Macrocíclicos/química , Compuestos Macrocíclicos/farmacocinética , Compuestos Macrocíclicos/farmacología , Ratones , Ratones Endogámicos BALB CRESUMEN
Oral factor XIa (FXIa) inhibitors may provide a promising new antithrombotic therapy with an improved benefit to bleeding risk profile over existing antithrombotic agents. Herein, we report application of a previously disclosed cyclic carbamate P1 linker which provided improved oral bioavailability in the imidazole-based 13-membered macrocycle to the 12-membered macrocycle. This resulted in identification of compound 4 with desired FXIa inhibitory potency and good oral bioavailability but high in vivo clearance. Further structure-activity relationship (SAR) studies of heterocyclic core modifications to replace the imidazole core as well as various linkers to the P1 group led to the discovery of compound 6f, a potent FXIa inhibitor with selectivity against most of the relevant serine proteases. Compound 6f also demonstrated excellent pharmacokinetics (PK) profile (high oral bioavailability and low clearance) in multiple preclinical species. Compound 6f achieved robust antithrombotic efficacy in a rabbit efficacy model at doses which preserved hemostasis.
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Factor XIa/antagonistas & inhibidores , Fibrinolíticos/administración & dosificación , Fibrinolíticos/farmacología , Administración Oral , Animales , Disponibilidad Biológica , Cristalografía por Rayos X , Perros , Evaluación Preclínica de Medicamentos , Factor XIa/química , Factor XIa/metabolismo , Fibrinolíticos/química , Fibrinolíticos/farmacocinética , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Compuestos Macrocíclicos/administración & dosificación , Compuestos Macrocíclicos/química , Compuestos Macrocíclicos/farmacocinética , Compuestos Macrocíclicos/farmacología , Modelos Moleculares , Conejos , Relación Estructura-ActividadRESUMEN
Repotrectinib, a next-generation ROS1/TRK/ALK tyrosine kinase inhibitor, overcomes resistance due to acquired solvent-front mutations involving ROS1, NTRK1-3, and ALK. A bioanalytical assay for quantification of repotrectinib in mouse plasma and seven tissue-related matrices (brain, liver, spleen, kidney, small intestinal tissue, small intestinal content, and testis homogenates) was developed and validated using liquid chromatography with tandem mass spectrometric detection in a high-throughput 96-well format. Protein precipitation was performed by adding acetonitrile, also containing the internal standard axitinib, to 10-µl samples for all matrices. Chromatographic separation of analytes was done on an ACQUITY UPLC® BEH C18 column by gradient elution using ammonium hydroxide in water and methanol. Compounds were monitored with positive electrospray ionization using a triple quadruple mass spectrometer in selected reaction monitoring mode. The method was successfully validated in the 1-1000 ng/ml calibration range. Precisions (intra- and interday) were in the range of 1.3-8.7% and accuracies were in between 90.5% and 107.3% for all levels in all matrices. The developed method was successfully applied to investigate the plasma pharmacokinetics and tissue accumulation of repotrectinib in wild-type mice.
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Compuestos Macrocíclicos/sangre , Compuestos Macrocíclicos/farmacocinética , Inhibidores de Proteínas Quinasas/sangre , Inhibidores de Proteínas Quinasas/farmacocinética , Pirazoles/sangre , Pirazoles/farmacocinética , Quinasa de Linfoma Anaplásico/antagonistas & inhibidores , Animales , Axitinib/química , Axitinib/normas , Bioensayo , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Límite de Detección , Compuestos Macrocíclicos/administración & dosificación , Ratones , Plasma/química , Inhibidores de Proteínas Quinasas/administración & dosificación , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Pirazoles/administración & dosificación , Receptor trkA/antagonistas & inhibidores , Reproducibilidad de los Resultados , Espectrometría de Masas en Tándem , Distribución TisularRESUMEN
The discovery of orally bioavailable FXIa inhibitors has been a challenge. Herein, we describe our efforts to address this challenge by optimization of our imidazole-based macrocyclic series. Our optimization strategy focused on modifications to the P2 prime, macrocyclic amide linker, and the imidazole scaffold. Replacing the amide of the macrocyclic linker with amide isosteres led to the discovery of substituted amine linkers which not only maintained FXIa binding affinity but also improved oral exposure in rats. Combining the optimized macrocyclic amine linker with a pyridine scaffold afforded compounds 23 and 24 that were orally bioavailable, single-digit nanomolar FXIa inhibitors with excellent selectivity against relevant blood coagulation enzymes.
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Aminas/química , Factor XIa/antagonistas & inhibidores , Compuestos Macrocíclicos/química , Inhibidores de Serina Proteinasa/síntesis química , Administración Oral , Animales , Sitios de Unión , Diseño de Fármacos , Factor XIa/metabolismo , Semivida , Compuestos Macrocíclicos/metabolismo , Compuestos Macrocíclicos/farmacocinética , Simulación de Dinámica Molecular , Estructura Terciaria de Proteína , Piridinas/química , Ratas , Inhibidores de Serina Proteinasa/metabolismo , Inhibidores de Serina Proteinasa/farmacocinética , Relación Estructura-ActividadRESUMEN
BACKGROUND: POL6014 is a novel, orally inhaled neutrophil elastase (NE) inhibitor in development for cystic fibrosis (CF). METHODS: Two studies, one in healthy volunteers (HVs, doses 20 to 960â¯mg) and one in subjects with CF (doses 80 to 320â¯mg) were conducted to evaluate the safety, tolerability and pharmacokinetics (PK) of single ascending doses of inhaled POL6014 with a Pari eFlow® nebuliser. PK was evaluated over a period of 24â¯h. In addition, NE activity in CF sputum was measured. RESULTS: After single doses, POL6014 was safe and well tolerated up to 480â¯mg in HVs and at all doses in subjects with CF. POL6014 showed a dose-linear PK profile in both populations with Cmax between 0.2 and 2.5⯵M in HVs and between 0.2 and 0.5⯵M in subjects with CF. Tmax was reached at approximately 2-3â¯h. Mean POL6014 levels in CF sputum rapidly reached 1000⯵M and were still above 10⯵M at 24â¯h. >1-log reduction of active NE was observed at 3â¯h after dosing. CONCLUSION: Inhalation of POL6014 can safely lead to high concentrations within the lung and simultaneously low plasma concentrations, allowing for a clear inhibition of NE in the sputum of subjects with CF after single dosing. TRIAL REGISTRATION: European Medicines Agency EudraCT-Nr. 2015-001618-83 and 2016-000493-38.
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Fibrosis Quística , Inhibidores Enzimáticos , Elastasa de Leucocito/antagonistas & inhibidores , Compuestos Macrocíclicos , Esputo/enzimología , Administración por Inhalación , Adulto , Fibrosis Quística/diagnóstico , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/fisiopatología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Pruebas de Enzimas/métodos , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/farmacocinética , Femenino , Voluntarios Sanos , Humanos , Pulmón/metabolismo , Pulmón/fisiopatología , Compuestos Macrocíclicos/administración & dosificación , Compuestos Macrocíclicos/efectos adversos , Compuestos Macrocíclicos/farmacocinética , Masculino , Nebulizadores y VaporizadoresRESUMEN
Drugs that accumulate in lysosomes reach very high tissue concentrations, which is evident in the high volume of distribution and often lower clearance of these compounds. Such a pharmacokinetic profile is beneficial for indications where high tissue penetration and a less frequent dosing regime is required. Here, we show how the level of lysosomotropic accumulation in cells can be predicted solely from molecular structure. To develop quantitative structure-activity relationship (QSAR) models, we used cellular accumulation data for 69 lysosomotropic macrocycles, the pharmaceutical class for which this type of prediction model is extremely valuable due to the importance of cellular accumulation for their anti-infective and anti-inflammatory applications as well as due to the fact that they are extremely difficult to model by computational methods because of their large size (Mw > 500). For the first time, we show that five levels of intracellular lysosomotropic accumulation (as measured by liquid chromatography coupled to tandem mass spectrometry-LC-MS/MS), from low/no to extremely high, can be predicted with 60% balanced accuracy solely from the compound's structure. Although largely built on macrocycles, the eight non-macrocyclic compounds that were added to the set were found to be well incorporated by the models, indicating their possible broader application. By uncovering the link between the molecular structure and cellular accumulation as the key process in tissue distribution of lysosomotropic compounds, these models are applicable for directing the drug discovery process and prioritizing the compounds for synthesis with fine-tuned accumulation properties, according to the desired pharmacokinetic profile.
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Biología Computacional/métodos , Lisosomas/química , Compuestos Macrocíclicos/farmacocinética , Cromatografía Liquida , Compuestos Macrocíclicos/química , Estructura Molecular , Relación Estructura-Actividad Cuantitativa , Espectrometría de Masas en Tándem , Distribución TisularRESUMEN
The pharmaceutical industry has focused mainly in the development of small-molecule entities intended for oral administration for the past decades. As a result, the majority of existing drugs address only a narrow range of biological targets. In the era of post-genomics, transcriptomics, and proteomics, there is an increasing interest on larger modulators of proteins that can span larger surfaces, access new therapeutic mechanisms of action, and provide greater target specificity. Traditional drug-like molecules developed using "rule-of-five" (Ro5) guidelines have been proven ineffective against a variety of challenging targets, such as protein-protein interactions, nucleic acid complexes, and antibacterial modalities. However, natural products are known to be effective at modulating such targets, leading to a renewed focus by medicinal chemists on investigating underrepresented chemical scaffolds associated with natural products. Here we describe recent efforts toward identification of novel natural cyclopeptides and macrocycles as well as selected medicinal chemistry strategies to increase drug-like properties or further exploration of their activity.
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Productos Biológicos/química , Compuestos Macrocíclicos/química , Péptidos Cíclicos/química , Antraquinonas/química , Antraquinonas/uso terapéutico , Disponibilidad Biológica , Productos Biológicos/farmacocinética , Productos Biológicos/uso terapéutico , Química Farmacéutica , Ciclosporina/química , Ciclosporina/uso terapéutico , Ciclotidas/química , Ciclotidas/uso terapéutico , Daptomicina/química , Daptomicina/uso terapéutico , Depsipéptidos/química , Depsipéptidos/uso terapéutico , Diseño de Fármacos , Descubrimiento de Drogas , Éteres Cíclicos/química , Éteres Cíclicos/uso terapéutico , Gramicidina/química , Gramicidina/uso terapéutico , Lipopéptidos/química , Lipopéptidos/uso terapéutico , Compuestos Macrocíclicos/farmacocinética , Compuestos Macrocíclicos/uso terapéutico , Macrólidos/química , Macrólidos/uso terapéutico , Compuestos Organofosforados/química , Compuestos Organofosforados/uso terapéutico , Oxazoles/química , Oxazoles/uso terapéutico , Péptidos/química , Péptidos/uso terapéutico , Péptidos Cíclicos/farmacocinética , Péptidos Cíclicos/uso terapéutico , Tiazoles/química , Tiazoles/uso terapéutico , Tiazolidinas/química , Tiazolidinas/uso terapéutico , omega-Conotoxinas/química , omega-Conotoxinas/uso terapéuticoRESUMEN
A Rhizopus sp. culture containing an endosymbiont partner ( Burkholderia sp.) was obtained through a citizen-science-based soil-collection program. An extract prepared from the pair of organisms exhibited strong inhibition of Ewing sarcoma cells and was selected for bioassay-guided fractionation. This led to the purification of rhizoxin (1), a potent antimitotic agent that inhibited microtubule polymerization, along with several new (2-5) and known (6) analogues of 1. The structures of 2-6 were established using a combination of NMR data analysis, while the configurations of the new stereocenters were determined using ROESY spectroscopy and comparison of GIAO-derived and experimental data for NMR chemical shift and 3 JHH coupling values. Whereas compound 1 showed modest selectivity for Ewing sarcoma cell lines carrying the EWSR1/ FLI1 fusion gene, the other compounds were determined to be inactive. Chemically, compound 2 stands out from other rhizoxin analogues because it is the first member of this class that is reported to contain a one-carbon-smaller 15-membered macrolactone system. Through a combination of experimental and computational tests, we determined that 2 is likely formed via an acid-catalyzed Meinwald rearrangement from 1 because of the mild acidic culture environment created by the Rhizopus sp. isolate and its symbiont.
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Compuestos Macrocíclicos/química , Compuestos Macrocíclicos/farmacocinética , Macrólidos/química , Macrólidos/farmacocinética , Estrés Fisiológico , Burkholderia/química , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Rhizopus/química , Sarcoma de Ewing/patología , Relación Estructura-Actividad , SimbiosisRESUMEN
Previously, we reported the discovery of macrocyclic peptide triazoles (cPTs) that bind to HIV-1 Env gp120, inhibit virus cell infection with nanomolar potencies, and cause irreversible virion inactivation. Given the appealing virus-killing activity of cPTs and resistance to protease cleavage observed in vitro, we here investigated in vivo pharmacokinetics of the cPT AAR029b. AAR029b was investigated both alone and encapsulated in a PEGylated liposome formulation that was designed to slowly release inhibitor. Pharmacokinetic analysis in rats showed that the half-life of FITC-AAR029b was substantial both alone and liposome-encapsulated, 2.92 and 8.87 hours, respectively. Importantly, liposome-encapsulated FITC-AAR029b exhibited a 15-fold reduced clearance rate from serum compared with the free FITC-cPT. This work thus demonstrated both the in vivo stability of cPT alone and the extent of pharmacokinetic enhancement via liposome encapsulation. The results obtained open the way to further develop cPTs as long-acting HIV-1 inactivators against HIV-1 infection.