RESUMEN
Human genetic evidence shows that PDE3B is associated with metabolic and dyslipidemia phenotypes. A number of PDE3 family selective inhibitors have been approved by the FDA for various indications; however, given the undesirable proarrhythmic effects in the heart, selectivity for PDE3B inhibition over closely related family members (such as PDE3A; 48% identity) is a critical consideration for development of PDE3B therapeutics. Selectivity for PDE3B over PDE3A may be achieved in a variety of ways, including properties intrinsic to the compound or tissue-selective targeting. The high (>95%) active site homology between PDE3A and B represents a massive obstacle for obtaining selectivity at the active site; however, utilization of libraries with high molecular diversity in high throughput screens may uncover selective chemical matter. Herein, we employed a DNA-encoded library screen to identify PDE3B-selective inhibitors and identified potent and selective boronic acid compounds bound at the active site.
Asunto(s)
ADN , Corazón , Humanos , Dominio Catalítico , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 3RESUMEN
GlaxoSmithKline and Astex Pharmaceuticals recently disclosed the discovery of the potent H-PGDS inhibitor GSK2894631A 1a (IC50 = 9.9 nM) as part of a fragment-based drug discovery collaboration with Astex Pharmaceuticals. This molecule exhibited good murine pharmacokinetics, allowing it to be utilized to explore H-PGDS pharmacology in vivo. Yet, with prolonged dosing at higher concentrations, 1a induced CNS toxicity. Looking to attenuate brain penetration in this series, aza-quinolines, were prepared with the intent of increasing polar surface area. Nitrogen substitutions at the 6- and 8-positions of the quinoline were discovered to be tolerated by the enzyme. Subsequent structure activity studies in these aza-quinoline scaffolds led to the identification of 1,8-naphthyridine 1y (IC50 = 9.4 nM) as a potent peripherally restricted H-PGDS inhibitor. Compound 1y is efficacious in four in vivo inflammatory models and exhibits no CNS toxicity.
Asunto(s)
Compuestos Aza/química , Inhibidores Enzimáticos/química , Quinolinas/química , Animales , Sitios de Unión , Encéfalo/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cristalografía por Rayos X , Estabilidad de Medicamentos , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Humanos , Oxidorreductasas Intramoleculares/antagonistas & inhibidores , Oxidorreductasas Intramoleculares/metabolismo , Cinética , Masculino , Ratones , Ratones Endogámicos C57BL , Simulación de Dinámica Molecular , Músculo Esquelético/química , Músculo Esquelético/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
With the goal of discovering more selective anti-inflammatory drugs, than COX inhibitors, to attenuate prostaglandin signaling, a fragment-based screen of hematopoietic prostaglandin D synthase was performed. The 76 crystallographic hits were sorted into similar groups, with the 3-cyano-quinoline 1a (FP IC50â¯=â¯220,000â¯nM, LEâ¯=â¯0.43) being a potent member of the 6,6-fused heterocyclic cluster. Employing SAR insights gained from structural comparisons of other H-PGDS fragment binding mode clusters, the initial hit 1a was converted into the 70-fold more potent quinoline 1d (IC50â¯=â¯3,100â¯nM, LEâ¯=â¯0.49). A systematic substitution of the amine moiety of 1d, utilizing structural information and array chemistry, with modifications to improve inhibitor stability, resulted in the identification of the 300-fold more active H-PGDS inhibitor tool compound 1bv (IC50â¯=â¯9.9â¯nM, LEâ¯=â¯0.42). This selective inhibitor exhibited good murine pharmacokinetics, dose-dependently attenuated PGD2 production in a mast cell degranulation assay and should be suitable to further explore H-PGDS biology.
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Oxidorreductasas Intramoleculares/antagonistas & inhibidores , Lipocalinas/antagonistas & inhibidores , Quinolinas/química , Quinolinas/farmacología , Animales , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacocinética , Humanos , Oxidorreductasas Intramoleculares/química , Oxidorreductasas Intramoleculares/metabolismo , Lipocalinas/química , Lipocalinas/metabolismo , Masculino , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Quinolinas/farmacocinéticaRESUMEN
Starting from the micromolar 8-quinoline carboxamide high-throughput screening hit 1a, a systematic exploration of the structure-activity relationships (SAR) of the 4-, 6-, and 8-substituents of the quinoline ring resulted in the identification of approximately 10-100-fold more potent human CD38 inhibitors. Several of these molecules also exhibited pharmacokinetic parameters suitable for in vivo animal studies, including low clearances and decent oral bioavailability. Two of these CD38 inhibitors, 1ah and 1ai, were shown to elevate NAD tissue levels in liver and muscle in a diet-induced obese (DIO) C57BL/6 mouse model. These inhibitor tool compounds will enable further biological studies of the CD38 enzyme as well as the investigation of the therapeutic implications of NAD enhancement in disease models of abnormally low NAD.
Asunto(s)
ADP-Ribosil Ciclasa 1/antagonistas & inhibidores , Amidas/química , Aminoquinolinas/química , NAD/metabolismo , Quinolinas/química , Amidas/síntesis química , Amidas/farmacología , Aminoquinolinas/síntesis química , Aminoquinolinas/farmacología , Animales , Disponibilidad Biológica , Cristalografía por Rayos X , Humanos , Hidrólisis , Hígado/metabolismo , Membranas Artificiales , Ratones Endogámicos C57BL , Modelos Moleculares , Músculo Esquelético/metabolismo , Obesidad/metabolismo , Permeabilidad , Conformación Proteica , Quinolinas/síntesis química , Quinolinas/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
hCD157 catalyzes the hydrolysis of nicotinamide riboside (NR) and nicotinic acid riboside (NAR). The release of nicotinamide or nicotinic acid from NR or NAR was confirmed by spectrophotometric, HPLC and NMR analyses. hCD157 is inactivated by a mechanism-based inhibitor, 2'-deoxy-2'-fluoro-nicotinamide arabinoside (fNR). Modification of the enzyme during the catalytic cycle by NR, NAR, or fNR increased the intrinsic protein fluorescence by approximately 50%. Pre-steady state and steady state data were used to derive a minimal kinetic scheme for the hydrolysis of NR. After initial complex formation a reversible step (360 and 30s(-1)) is followed by a slow irreversible step (0.1s(-1)) that defined the rate limiting step, or kcat. The calculated KMapp value for NR in the hydrolytic reaction is 6nM. The values of the kinetic constants suggest that one biological function of cell-surface hCD157 is to bind and slowly hydrolyze NR, possibly converting it to a ligand-activated receptor. Differences in substrate preference between hCD157 and hCD38 were rationalized through a comparison of the crystal structures of the two proteins. This comparison identified several residues in hCD157 (F108 and F173) that can potentially hinder the binding of dinucleotide substrates (NAD+).
Asunto(s)
ADP-Ribosil Ciclasa/química , Antígenos CD/química , Niacinamida/análogos & derivados , Ribonucleósidos/química , ADP-Ribosil Ciclasa/genética , ADP-Ribosil Ciclasa/metabolismo , Animales , Antígenos CD/genética , Antígenos CD/metabolismo , Células CHO , Catálisis , Cricetinae , Cricetulus , Proteínas Ligadas a GPI/química , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/metabolismo , Humanos , Hidrólisis , Cinética , Niacinamida/química , Niacinamida/genética , Niacinamida/metabolismo , Resonancia Magnética Nuclear Biomolecular , Compuestos de Piridinio , Ribonucleósidos/genética , Ribonucleósidos/metabolismoRESUMEN
1-(1,3,5-Triazin-yl)piperidine-4-carboxamide inhibitors of soluble epoxide hydrolase were identified from high through-put screening using encoded library technology. The triazine heterocycle proved to be a critical functional group, essential for high potency and P450 selectivity. Phenyl group substitution was important for reducing clearance, and establishing good oral exposure. Based on this lead optimization work, 1-[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]-N-{[[4-bromo-2-(trifluoromethoxy)]-phenyl]methyl}-4-piperidinecarboxamide (27) was identified as a useful tool compound for in vivo investigation. Robust effects on a serum biomarker, 9, 10-epoxyoctadec-12(Z)-enoic acid (the epoxide derived from linoleic acid) were observed, which provided evidence of robust in vivo target engagement and the suitability of 27 as a tool compound for study in various disease models.
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Amidas/química , Amidas/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Epóxido Hidrolasas/antagonistas & inhibidores , Piperidinas/química , Piperidinas/farmacología , Amidas/síntesis química , Descubrimiento de Drogas , Inhibidores Enzimáticos/síntesis química , Epóxido Hidrolasas/metabolismo , Humanos , Modelos Moleculares , Piperidinas/síntesis química , Relación Estructura-Actividad , Triazinas/síntesis química , Triazinas/química , Triazinas/farmacologíaRESUMEN
Proline-specific dipeptidyl peptidases (DPPs) are emerging targets for drug development. DPP4 inhibitors are approved in many countries, and other dipeptidyl peptidases are often referred to as DPP4 activity- and/or structure-homologues (DASH). Members of the DASH family have overlapping substrate specificities, and, even though they share low sequence identity, therapeutic or clinical cross-reactivity is a concern. Here, we report the structure of human DPP7 and its complex with a selective inhibitor Dab-Pip (L-2,4-diaminobutyryl-piperidinamide) and compare it with that of DPP4. Both enzymes share a common catalytic domain (α/ß-hydrolase). The catalytic pocket is located in the interior of DPP7, deep inside the cleft between the two domains. Substrates might access the active site via a narrow tunnel. The DPP7 catalytic triad is completely conserved and comprises Ser162, Asp418 and His443 (corresponding to Ser630, Asp708 and His740 in DPP4), while other residues lining the catalytic pockets differ considerably. The "specificity domains" are structurally also completely different exhibiting a ß-propeller fold in DPP4 compared to a rare, completely helical fold in DPP7. Comparing the structures of DPP7 and DPP4 allows the design of specific inhibitors and thus the development of less cross-reactive drugs. Furthermore, the reported DPP7 structures shed some light onto the evolutionary relationship of prolyl-specific peptidases through the analysis of the architectural organization of their domains.
Asunto(s)
Dipeptidil Peptidasa 4/genética , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/química , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/metabolismo , Prolina/química , Aminoácidos/química , Animales , Secuencia de Bases , Células CHO , Catálisis , Dominio Catalítico , Cricetinae , Dimerización , Dipeptidil Peptidasa 4/química , Evolución Molecular , Humanos , Insectos , Datos de Secuencia Molecular , Unión Proteica , Estructura Terciaria de Proteína , Especificidad por SustratoRESUMEN
Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is activated in response to a variety of endoplasmic reticulum stresses implicated in numerous disease states. Evidence that PERK is implicated in tumorigenesis and cancer cell survival stimulated our search for small molecule inhibitors. Through screening and lead optimization using the human PERK crystal structure, we discovered compound 38 (GSK2606414), an orally available, potent, and selective PERK inhibitor. Compound 38 inhibits PERK activation in cells and inhibits the growth of a human tumor xenograft in mice.
Asunto(s)
Adenina/análogos & derivados , Antineoplásicos/síntesis química , Indoles/síntesis química , Pirimidinas/síntesis química , Pirroles/síntesis química , eIF-2 Quinasa/antagonistas & inhibidores , Adenina/síntesis química , Adenina/química , Adenina/farmacología , Administración Oral , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Disponibilidad Biológica , Línea Celular Tumoral , Cristalografía por Rayos X , Perros , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Indoles/química , Indoles/farmacología , Masculino , Ratones , Ratones Desnudos , Modelos Moleculares , Trasplante de Neoplasias , Fosforilación , Conformación Proteica , Pirimidinas/química , Pirimidinas/farmacología , Pirroles/química , Pirroles/farmacología , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Trasplante HeterólogoRESUMEN
The optimization of imidazo[1,2-a]pyridine inhibitors as potent and selective inhibitors of IGF-1R is presented. Further optimization of oral exposure in mice is also discussed. Detailed selectivity, in vitro activity, and in vivo PK profiles of an optimized compound is also highlighted.
Asunto(s)
Química Farmacéutica/métodos , Piridinas/química , Receptor IGF Tipo 1/antagonistas & inhibidores , Receptor IGF Tipo 1/química , Administración Oral , Compuestos de Anilina/química , Animales , Línea Celular Tumoral , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Ratones , Modelos Químicos , Conformación Molecular , Piridinas/síntesis química , Piridinas/farmacología , Receptor de Insulina/metabolismoRESUMEN
Two new series of potent and selective dual EGFR/ErbB-2 kinase inhibitors derived from novel thienopyrimidine cores have been identified. Isomeric thienopyrimidine cores were evaluated as isosteres for a 4-anilinoquinazoline core and several analogs containing the thieno[3,2-d]pyrimidine core showed anti-proliferative activity with IC(50) values less than 1 microM against human tumor cells in vitro.
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Antineoplásicos/farmacología , Química Farmacéutica/métodos , Receptores ErbB/química , Pirimidinas/química , Receptor ErbB-2/antagonistas & inhibidores , Antineoplásicos/síntesis química , Línea Celular Tumoral , Proliferación Celular , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/farmacología , Humanos , Concentración 50 Inhibidora , Lapatinib , Modelos Químicos , Conformación Molecular , Quinazolinas/farmacologíaRESUMEN
The SAR of C5' functional groups with terminal basic amines at the C6 aniline of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidines is reported. Examples demonstrate potent inhibition of IGF-1R with 1000-fold selectivity over JNK1 and 3 in enzymatic assays.
Asunto(s)
MAP Quinasa Quinasa 4/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Pirroles/farmacología , Receptor IGF Tipo 1/antagonistas & inhibidores , Modelos Moleculares , Pirimidinas/química , Pirroles/química , Relación Estructura-ActividadRESUMEN
A novel series of pyrazolo[1,5-b]pyridazines have been synthesized and identified as cyclin dependant kinase inhibitors potentially useful for the treatment of solid tumors. Modification of the hinge-binding amine or the C(2)- and C(6)-substitutions on the pyrazolopyridazine core provided potent inhibitors of CDK4 and demonstrated enzyme selectivity against VEGFR-2 and GSK3beta.
Asunto(s)
Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Piridazinas/síntesis química , Piridazinas/farmacología , Evaluación Preclínica de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3 beta , Modelos Moleculares , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidoresRESUMEN
An X-ray crystal structure is reported for the novel enhanced-affinity glucocorticoid agonist fluticasone furoate (FF) in the ligand binding domain of the glucocorticoid receptor. Comparison of this structure with those of dexamethasone and fluticasone propionate shows the 17 alpha furoate ester to occupy more fully the lipophilic 17 alpha pocket on the receptor, which may account for the enhanced glucocorticoid receptor binding of FF.
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Androstadienos/química , Receptores de Glucocorticoides/agonistas , Receptores de Glucocorticoides/química , Sitios de Unión , Cristalografía por Rayos X , Humanos , Modelos Moleculares , Coactivador 2 del Receptor Nuclear/química , Conformación ProteicaRESUMEN
Analysis of the x-ray crystal structure of mono-substituted acetylenic thienopyrimidine 6 complexed with the ErbB family enzyme ErbB-4 revealed a covalent bond between the terminal carbon of the acetylene moiety and the sulfhydryl group of Cys-803 at the solvent interface. The identification of this covalent adduct suggested that acetylenic thienopyrimidine 6 and related analogs might also be capable of forming an analogous covalent adduct with EGFR, which has a conserved cysteine (797) near the ATP binding pocket. To test this hypothesis, we treated a truncated, catalytically competent form of EGFR (678-1020) with a structurally related propargylic amine (8). An investigation of the resulting complex by mass spectrometry revealed the formation of a covalent complex of thienopyrimidine 8 with Cys-797 of EGFR. This finding enabled us to readily assess the irreversibility of various inhibitors and also facilitated a structure-activity relationship understanding of the covalent modifying potential and biological activity of a series of acetylenic thienopyrimidine compounds with potent antitumor activity. Several ErbB family enzyme and cell potent 6-ethynyl thienopyrimidine kinase inhibitors were found to form covalent adducts with EGFR.
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Alquinos/metabolismo , Compuestos de Anilina/metabolismo , Receptores ErbB/metabolismo , Modelos Moleculares , Pirimidinas/metabolismo , Animales , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Femenino , Isatina/análogos & derivados , Isatina/metabolismo , Espectrometría de Masas , Ratones , Ratones SCID , Estructura Molecular , Pirimidinas/toxicidad , Proteínas Tirosina Quinasas Receptoras/metabolismo , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Obtaining diffraction-quality crystals has long been a bottleneck in solving the three-dimensional structures of proteins. Often proteins may be stabilized when they are complexed with a substrate, nucleic acid, cofactor or small molecule. These ligands, on the other hand, have the potential to induce significant conformational changes to the protein and ab initio screening may be required to find a new crystal form. This paper presents an overview of strategies in the following areas for obtaining crystals of protein-ligand complexes: (i) co-expression of the protein with the ligands of interest, (ii) use of the ligands during protein purification, (iii) cocrystallization and (iv) soaks.
Asunto(s)
Cristalización , Cristalografía por Rayos X/métodos , Proteínas/química , Animales , Sitios de Unión , Proteínas Portadoras/química , Humanos , Ligandos , Liposomas/química , Conformación Molecular , Mutación , Receptores Androgénicos/química , Receptores de Glucocorticoides/química , Receptores de Mineralocorticoides/química , TemperaturaRESUMEN
Anilinopyrazoles as CDK2 inhibitors can adopt multiple binding modes depending on the substituents at the 5-position of the pyrazole ring, based on CDK2/cyclin A crystallographic studies. Three commercially available docking programs, FlexX, GOLD, and LigandFit, were tested with 63 anilinopyrazole analogues in an attempt to reproduce the binding modes observed in the crystal structures. Each docking program gave different ligand conformations depending on the scoring or energy functions used. FlexX/drugscore, GOLD/chemscore, and LigandFit/plp were the best combinations of each docking program in reproducing the ligand conformations observed in the crystal structures. The 63 analogues were divided into two groups, type-A and type-B, depending on the substituent at the 5-position of the pyrazole ring. Although an alternate binding mode, observed in a crystal structure of one type-B compound, could not be reproduced with any of the above docking/scoring combinations, GOLD, with a template constraint based on the crystal structure coordinates, was able to reproduce the pose. As for type-A compounds, all docking conditions yielded similar poses to those observed in crystal structures. When predicting activities by scoring programs, the combination of docking with LigandFit/plp and scoring with LIGSCORE1_CFF gave the best correlation coefficient (r=0.60) between experimental pIC50 values and top-ranked rescores of 30 poses of each compound. With regard to type-A compounds, the correlation was 0.69. However, when 11 compounds, whose top-ranked rescored poses did not demonstrate the correct binding modes in reference to the crystal structure, were removed, the correlation rose to 0.75. Consequently, predicting activity on the basis of correct binding modes was found to be reliable.
Asunto(s)
Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Evaluación Preclínica de Medicamentos/métodos , Pirazoles/química , Algoritmos , Química Farmacéutica/métodos , Cristalografía por Rayos X , Bases de Datos de Proteínas , Diseño de Fármacos , Industria Farmacéutica/métodos , Estudios de Evaluación como Asunto , Humanos , Ligandos , Unión Proteica , Estructura Terciaria de Proteína , Programas InformáticosRESUMEN
The identification and hit-to-lead exploration of a novel, potent and selective series of substituted benzimidazole-thiophene carbonitrile inhibitors of IKK-epsilon kinase is described. Compound 12e was identified with an IKK-epsilon enzyme potency of pIC(50) 7.4, and has a highly encouraging wider selectivity profile, including selectivity within the IKK kinase family.
Asunto(s)
Bencimidazoles/síntesis química , Bencimidazoles/farmacología , Quinasa I-kappa B/antagonistas & inhibidores , Nitrilos/síntesis química , Nitrilos/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Tiofenos/síntesis química , Tiofenos/farmacología , Enlace de Hidrógeno , Cinética , Modelos Moleculares , Tiofenos/química , Difracción de Rayos XRESUMEN
Starting from a potent pantolactone ketoamide cathepsin K inhibitor discovered from structural screening, conversion of the lactone scaffold to a pyrrolidine scaffold allowed exploration of the S(3) subsite of cathepsin K. Manipulation of P3 and P1' groups afforded potent inhibitors with drug-like properties.
Asunto(s)
Amidas , Catepsinas/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa , Cetonas , Pirrolidinas , Amidas/síntesis química , Amidas/farmacocinética , Amidas/farmacología , Sitios de Unión , Catepsina K , Catepsinas/química , Cristalografía por Rayos X , Inhibidores de Cisteína Proteinasa/síntesis química , Inhibidores de Cisteína Proteinasa/farmacocinética , Inhibidores de Cisteína Proteinasa/farmacología , Humanos , Concentración 50 Inhibidora , Cetonas/síntesis química , Cetonas/farmacocinética , Cetonas/farmacología , Modelos Moleculares , Estructura Molecular , Pirrolidinas/síntesis química , Pirrolidinas/farmacocinética , Pirrolidinas/farmacología , Inhibidores de Serina Proteinasa , Relación Estructura-ActividadRESUMEN
Starting from potent aldehyde inhibitors with poor drug properties, derivatization to semicarbazones led to the identification of a series of semicarbazone-based cathepsin K inhibitors with greater solubility and better pharmacokinetic profiles than their parent aldehydes. Furthermore, a representative semicarbazone inhibitor attenuated bone resorption in an ex vivo rat calvarial bone resorption model. However, based on enzyme inhibition comparisons at neutral pH, semicarbazone hydrolysis rates, and 13C NMR experiments, these semicarbazones probably function as prodrugs of aldehydes.
Asunto(s)
Aldehídos/química , Catepsinas/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Semicarbazonas/farmacología , Animales , Catepsina K , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Concentración de Iones de Hidrógeno , Hidrólisis , Modelos Moleculares , Conformación Molecular , Profármacos/síntesis química , Profármacos/química , Profármacos/farmacología , Ratas , Semicarbazonas/síntesis química , Semicarbazonas/química , Solubilidad , Relación Estructura-ActividadRESUMEN
An orally bioavailable series of ketoamide-based cathepsin K inhibitors with good pharmacokinetic properties has been identified. Starting from a potent inhibitor endowed with poor drug properties, conformational constraint of the P(2)-P(3) linker and modifications to P(1') elements led to an enhancement in potency, solubility, clearance, and bioavailability. These optimized inhibitors attenuated bone resorption in a rat TPTX hypocalcemic bone resorption model.