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1.
Drug Metab Dispos ; 52(3): 198-209, 2024 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-38123948

RESUMEN

Microphysiological systems (MPS) are comprised of one or multiple cell types of human or animal origins that mimic the biochemical/electrical/mechanical responses and blood-tissue barrier properties of the cells observed within a complex organ. The goal of incorporating these in vitro systems is to expedite and advance the drug discovery and development paradigm with improved predictive and translational capabilities. Considering the industry need for improved efficiency and the broad challenges of model qualification and acceptance, the International Consortium for Innovation and Quality (IQ) founded an IQ MPS working group in 2014 and Affiliate in 2018. This group connects thought leaders and end users, provides a forum for crosspharma collaboration, and engages with regulators to qualify translationally relevant MPS models. To understand how pharmaceutical companies are using MPS, the IQ MPS Affiliate conducted two surveys in 2019, survey 1, and 2021, survey 2, which differed slightly in the scope of definition of the complex in vitro models under question. The surveys captured demographics, resourcing, rank order for organs of interest, compound modalities tested, and MPS organ-specific questions, including nonclinical species needs and cell types. The major focus of this manuscript is on results from survey 2, where we specifically highlight the context of use for MPS within safety, pharmacology, or absorption, disposition, metabolism, and excretion and discuss considerations for including MPS data in regulatory submissions. In summary, these data provide valuable insights for developers, regulators, and pharma, offering a view into current industry practices and future considerations while highlighting key challenges impacting MPS adoption. SIGNIFICANCE STATEMENT: The application of microphysiological systems (MPS) represents a growing area of interest in the drug discovery and development framework. This study surveyed 20+ pharma companies to understand resourcing, current areas of application, and the key challenges and barriers to internal MPS adoption. These results will provide regulators, tech providers, and pharma industry leaders a starting point to assess the current state of MPS applications along with key learnings to effectively realize the potential of MPS as an emerging technology.


Asunto(s)
Industria Farmacéutica , Sistemas Microfisiológicos , Animales , Humanos , Descubrimiento de Drogas
2.
Xenobiotica ; 51(8): 933-948, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-34151691

RESUMEN

FXIa-6f is a high affinity, orally bioavailable macrocyclic FXIa inhibitor with antithrombotic activity in preclinical species.The objectives of this study were to characterize the in vitro metabolism, determine circulating metabolites in pre-clinical species, and examine the disposition of the compound in a bile duct-cannulated rat study (BDC) study to inform clinical development of the compound and the medicinal chemistry approach to identify molecules with improved properties.Across species, metabolic pathways included several oxidative metabolites, including hydroxylated metabolites on the macrocycle or P1 region, descarbamoylation of the methyl carbamate side chain, and a glutathione conjugate on the 2,6-difluoro-3-chlorophenyl ring.In BDC rat, the absorbed dose of [3H]FXIa-6f was cleared mainly by metabolism, with excretion of drug-related material in the bile, mostly as metabolites.In all preclinical species, the parent drug was the primary drug-related component in circulation, but the species differences in the metabolic pathways observed in vitro were reflected in the plasma, where M6, a descarbamoylated metabolite, was more prominent in rat plasma, and M9, a hydroxylated metabolite, was more prominent in monkey plasma. Based on the available data, the human metabolism appears to be most similar to monkey.


Asunto(s)
Bilis , Animales , Ratas
3.
Xenobiotica ; 50(6): 621-629, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-31566996

RESUMEN

Accurate prediction of in vivo metabolic pathways in humans can be challenging because in vitro liver matrices may fail to produce certain in vivo metabolites.Rat and human spheroids, generated from cryopreserved hepatocytes in media that contained minimal amount of serum, maintained morphology, viability and cytochrome P450 (CYP) activities for at least a week without media exchange.With spheroid cultures, multiple Phase I and Phase II metabolites were observed in rat and human spheroid cultures that were incubated with loratadine (LOR) for multiple days. Consistent with in vivo observations, 3-hydroxydesloratadine, (3-OH-DL), along with its glucuronide, were observed in human spheroids, but not in rat spheroids. Interestingly, the putative intermediate metabolite leading to 3-OH-DL, DL-N-glucuronide, was observed in incubations with both rat and human spheroids. In conclusion, hepatocyte spheroid were capable of recapitulating the inter-species differences in metabolism between human and rat for LOR, therefore, it may represent a viable model for studying complex metabolic pathways.


Asunto(s)
Loratadina/metabolismo , Esferoides Celulares/metabolismo , Animales , Glucurónidos , Hepatocitos/metabolismo , Humanos , Loratadina/análogos & derivados , Masculino , Redes y Vías Metabólicas , Ratas
4.
Bioorg Med Chem Lett ; 24(5): 1294-8, 2014 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-24513044

RESUMEN

Spiropiperidine indoline-substituted diaryl ureas had been identified as antagonists of the P2Y1 receptor. Enhancements in potency were realized through the introduction of a 7-hydroxyl substitution on the spiropiperidinylindoline chemotype. SAR studies were conducted to improve PK and potency, resulting in the identification of compound 3e, a potent, orally bioavailable P2Y1 antagonist with a suitable PK profile in preclinical species. Compound 3e demonstrated a robust antithrombotic effect in vivo and improved bleeding risk profile compared to the P2Y12 antagonist clopidogrel in rat efficacy/bleeding models.


Asunto(s)
Compuestos de Fenilurea/química , Inhibidores de Agregación Plaquetaria/química , Antagonistas del Receptor Purinérgico P2Y/química , Receptores Purinérgicos P2Y1/química , Tiazoles/química , Urea/análogos & derivados , Administración Oral , Animales , Perros , Semivida , Macaca fascicularis , Compuestos de Fenilurea/farmacocinética , Compuestos de Fenilurea/farmacología , Compuestos de Fenilurea/uso terapéutico , Agregación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/farmacocinética , Inhibidores de Agregación Plaquetaria/farmacología , Inhibidores de Agregación Plaquetaria/uso terapéutico , Antagonistas del Receptor Purinérgico P2Y/farmacocinética , Antagonistas del Receptor Purinérgico P2Y/farmacología , Antagonistas del Receptor Purinérgico P2Y/uso terapéutico , Ratas , Receptores Purinérgicos P2Y1/metabolismo , Relación Estructura-Actividad , Tiazoles/farmacocinética , Tiazoles/farmacología , Tiazoles/uso terapéutico , Trombosis/tratamiento farmacológico , Urea/farmacocinética , Urea/farmacología , Urea/uso terapéutico
5.
J Med Chem ; 63(13): 7226-7242, 2020 07 09.
Artículo en Inglés | MEDLINE | ID: mdl-32456431

RESUMEN

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.


Asunto(s)
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-Actividad
6.
J Med Chem ; 60(23): 9703-9723, 2017 12 14.
Artículo en Inglés | MEDLINE | ID: mdl-29077405

RESUMEN

Factor XIa (FXIa) is a blood coagulation enzyme that is involved in the amplification of thrombin generation. Mounting evidence suggests that direct inhibition of FXIa can block pathologic thrombus formation while preserving normal hemostasis. Preclinical studies using a variety of approaches to reduce FXIa activity, including direct inhibitors of FXIa, have demonstrated good antithrombotic efficacy without increasing bleeding. On the basis of this potential, we targeted our efforts at identifying potent inhibitors of FXIa with a focus on discovering an acute antithrombotic agent for use in a hospital setting. Herein we describe the discovery of a potent FXIa clinical candidate, 55 (FXIa Ki = 0.7 nM), with excellent preclinical efficacy in thrombosis models and aqueous solubility suitable for intravenous administration. BMS-962212 is a reversible, direct, and highly selective small molecule inhibitor of FXIa.


Asunto(s)
Anticoagulantes/química , Anticoagulantes/uso terapéutico , Factor XIa/antagonistas & inhibidores , Isoquinolinas/química , Isoquinolinas/uso terapéutico , Trombosis/tratamiento farmacológico , para-Aminobenzoatos/química , para-Aminobenzoatos/uso terapéutico , Animales , Anticoagulantes/farmacocinética , Anticoagulantes/farmacología , Coagulación Sanguínea/efectos de los fármacos , Cristalografía por Rayos X , Perros , Descubrimiento de Drogas , Factor XIa/química , Factor XIa/metabolismo , Humanos , Isoquinolinas/farmacocinética , Isoquinolinas/farmacología , Masculino , Simulación del Acoplamiento Molecular , Conejos , Ratas , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacocinética , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Trombosis/sangre , para-Aminobenzoatos/farmacocinética , para-Aminobenzoatos/farmacología
7.
J Am Soc Mass Spectrom ; 17(1): 51-55, 2006 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-16352440

RESUMEN

Hydrogen cyanide (HCN) for use in ion preparation can be generated in the gas phase by the neutral-neutral reaction of trimethylsilyl cyanide (Me(3)SiCN) and water in a flowing afterglow mass spectrometer. We demonstrate that the approach can be used to generate a wide range of HCN solvated ions such as F(-)(HCN), Cl(-)(HCN), CN(-)(HCN), PhNO(2)(.-)(HCN), Me(3)SiO(-)(HCN),and PhSiF(4)(-)(HCN), many of which are otherwise difficult to generate. The bond dissociation energy of CN(-)(HCN), generated by using this approach, has been measured by using energy-resolved collision-induced issociation (CID) to be 0.87 +/- 0.07 eV.

8.
ChemMedChem ; 9(10): 2327-43, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-24989964

RESUMEN

Current antithrombotic discovery efforts target compounds that are highly efficacious in thrombus reduction with less bleeding liability than the standard of care. Preclinical data suggest that P2Y1 antagonists may have lower bleeding liabilities than P2Y12 antagonists while providing similar antithrombotic efficacy. This article describes our continuous SAR efforts in a series of 7-hydroxyindolinyl diaryl ureas. When dosed orally, 4-trifluoromethyl-7-hydroxy-3,3-dimethylindolinyl analogue 4 was highly efficacious in a model of arterial thrombosis in rats with limited bleeding. The chemically labile CF3 group in 4 was then transformed to various groups via a novel one-step synthesis, yielding a series of potent P2Y1 antagonists. Among them, the 4-benzothiazole-substituted indolines had desirable PK properties in rats, specifically, low clearance and small volume of distribution. In addition, compound 40 had high i.v. exposure and modest bioavailability, giving it the best overall profile.


Asunto(s)
Antagonistas del Receptor Purinérgico P2Y/farmacología , Urea/análogos & derivados , Animales , Humanos , Espectroscopía de Resonancia Magnética , Antagonistas del Receptor Purinérgico P2Y/farmacocinética , Espectrometría de Masa por Ionización de Electrospray , Urea/farmacocinética , Urea/farmacología
9.
J Mass Spectrom ; 47(2): 263-70, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22359338

RESUMEN

Mass spectral libraries represent versatile tools for the identification of small bioorganic molecules. Libraries based on electron impact spectra are rated robust and transferable. Tandem mass spectral libraries are often considered to work properly only on the instrument that has been used to build the library. An exception from that rule is the 'Wiley Registry of Tandem Mass Spectral Data, MSforID'. In various studies with data sets from different kinds of tandem mass spectrometric instruments, the outstanding sensitivity and robustness of this tandem mass spectral library search approach was demonstrated. The instrumental platforms tested, however, mainly included various tandem-in-space instruments. Herein, the results of a multicenter study with a focus on upfront and tandem-in-time fragmentation are presented. Five laboratories participated and provided fragment ion mass spectra from the following types of mass spectrometers: time-of-flight (TOF), quadrupole-hexapole-TOF, linear ion trap (LIT), 3-D ion trap and LIT-Orbitrap. A total number of 1231 fragment ion mass spectra were collected from 20 test compounds (amiloride, buphenin, cinchocaine, cyclizine, desipramine, dihydroergotamine, dyxirazine, dosulepin, ergotamine, ethambutol, etofylline, mefruside, metoclopramide, phenazone, phentermine, phenytoin, sulfamethoxazole, sulfamoxole, sulthiame and tetracycline) on seven electrospray ionization instruments using 18 different instrumental configurations for fragmentation. For 1222 spectra (99.3%), the correct compound was retrieved as the best matching compound. Classified matches (matches with 'relative average match probability' >40.0) were obtained for 1207 spectra (98.1%). This high percentage of correct identifications clearly supports the hypothesis that the tandem mass spectral library approach tested is a robust and universal identification tool.


Asunto(s)
Bases de Datos Factuales , Espectrometría de Masas en Tándem/instrumentación , Espectrometría de Masas en Tándem/métodos , Preparaciones Farmacéuticas/química , Espectrometría de Masa por Ionización de Electrospray/instrumentación , Espectrometría de Masa por Ionización de Electrospray/métodos
10.
J Org Chem ; 72(2): 494-501, 2007 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-17221966

RESUMEN

This work describes studies of the electron-promoted Cope cyclization of 2,5-phenyl-1,5-hexadiene radical anions in a flowing afterglow triple quadrupole mass spectrometer. The electronic properties of the hexadienes have been systematically modified by using aromatic substituents at the 2- and 5-positions of the hexedienes, including those with nitro, trifluoromethyl, fluoro, chloro, and acetyl groups. Ions were formed by the thermal attachment of electrons in the gas phase. Structures of the molecular radical anions were probed to determine whether they undergo cyclization to a cyclohexane-1,4-diyl anion structure by examining chemical reactivity with neutral reagents including carbon dioxide, carbon disulfide, and nitric oxide. First-order rate constants for the reactions of ions were measured, and the reaction efficiencies were determined. Based on the reactivity results, a thermochemical model has been developed, which predicts the reaction thermochemistry by using thermochemical properties of model systems. The observed reactivity from ion-molecule reactions and the study of reaction rates show that the ion of 2,5-dicyanohexadiene and 2,5-di(4,4'-trifluoromethyl phenyl)-1,5-hexadiene undergo Cope cyclization, whereas the radical anions having substituents such as the fluoro, nitro, chloro, and acetyl groups do not.

11.
Mass Spectrom Rev ; 25(1): 112-26, 2006.
Artículo en Inglés | MEDLINE | ID: mdl-16138298

RESUMEN

Nitric oxide is not only an important biological molecule with varied indispensable physiological roles but also shows interesting chemical reactivity both in gas-phase and solution phase. Even though it is a small molecule with an extremely low electron affinity, the reactivity of NO in the gas-phase is not just limited to electron-transfer or adduct formation. NO can behave both as an electrophile with closed-shell anions or as a radical with open-shell anions. Its reactivity with open-shell anions is characteristic and varied leading to interesting rearrangements. Nitric oxide anion undergoes spin-forbidden proton transfer with strong acids. Also, the ability of NO to serve both as one-electron or three-electron donor ligand can result in adduct formation or substitution reactions with transition metal complexes.


Asunto(s)
Aniones/química , Gases/química , Óxido Nítrico/química
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