RESUMEN
In our efforts to identify orally bioavailable CGRP receptor antagonists, we previously discovered a novel series of orally available azepinone derivatives that unfortunately also exhibited the unwanted property of potent time-dependent human CYP3A4 inhibition. Through heterocyclic replacement of the indazole ring, we discovered a series of heterocycle derivatives as high-affinity CGRP receptor antagonists. Some of them showed reasonable oral exposures, and the imidazolone derivatives that showed good oral exposure also exhibited substantially reduced time-dependent CYP3A4 inhibition. Several compounds showed strong in vivo efficacy in our marmoset facial blood flow assay with up to 87% inhibition of CGRP-induced activity. However, oral bioavailability generally remained low, emphasizing the challenges we and others encountered in discovering clinical development candidates for this difficult Class B GPCR target.
Asunto(s)
Azepinas/farmacología , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/farmacología , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismo , Azepinas/síntesis química , Azepinas/química , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/síntesis química , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/química , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Calcitonin gene-related peptide (CGRP) receptor antagonists have been shown clinically to be effective treatments for migraine. Zavegepant (BHV-3500, BMS-742413) is a high affinity antagonist of the CGRP receptor (hCGRP Ki = 0.023 nM) that has demonstrated efficacy in the acute treatment of migraine with intranasal delivery in a Phase 2/3 trial, despite showing low oral bioavailability in rats (FPO = 1.7%). Using zavegepant as a template, we sought to improve oral bioavailability through a series of azepinones which were designed in an attempt to reduce the number of rotatable bonds. These efforts led to the discovery of compound 21 which was able to mostly maintain high affinity binding (hCGRP Ki = 0.100 nM) and in vivo efficacy in the marmoset facial blood flow assay, while greatly improving oral bioavailability (rat FPO = 17%).
Asunto(s)
Azepinas/farmacología , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/farmacología , Indazoles/farmacología , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismo , Azepinas/química , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/química , Relación Dosis-Respuesta a Droga , Humanos , Indazoles/química , Estructura Molecular , Relación Estructura-ActividadRESUMEN
PURPOSE: To describe a stepwise approach to evaluate the pH effect for a weakly basic drug by in vitro, in vivo and in silico techniques and identify a viable mitigation strategy that addresses the risk. METHODS: Clinical studies included assessment of the pH effect with famotidine. In vitro dissolution was evaluated in various biorelevant media and in a pH-shift test. PK studies in dogs were conducted under pentagastrin or famotidine pre-treatment and GastroPlus was employed to model human and dog PK data and simulate the performance in human. RESULTS: Clinical data indicated considerable pH dependent absorption of the drug when dosed in the presence of H2-antagonists. In vitro dissolution and in vivo dog data confirmed that the observed pH effect was due to reduced dissolution rate and lower solubility at increased gastric and intestinal pH. A salt form was identified to overcome the effect by providing fast dissolution and prolonged supersaturation. GastroPlus simulations predicted a mitigation of the pH effect by the salt. CONCLUSIONS: The drug exhibited a strong pH-effect in humans. The in vitro, in vivo and modeling approach provides a systematic workflow to evaluate the risk of a new drug and identify a strategy able to mitigate the risk.
Asunto(s)
Antiulcerosos/farmacocinética , Simulación por Computador , Composición de Medicamentos/métodos , Famotidina/farmacocinética , Absorción Intestinal , Modelos Biológicos , Administración Oral , Animales , Antiulcerosos/administración & dosificación , Disponibilidad Biológica , Perros , Famotidina/administración & dosificación , Femenino , Humanos , Concentración de Iones de Hidrógeno , MasculinoRESUMEN
Influenza nucleoprotein (NP) plays multiple roles in the virus life cycle, including an essential function in viral replication as an integral component of the ribonucleoprotein complex, associating with viral RNA and polymerase within the viral core. The multifunctional nature of NP makes it an attractive target for antiviral intervention, and inhibitors targeting this protein have recently been reported. In a parallel effort, we discovered a structurally similar series of influenza replication inhibitors and show that they interfere with NP-dependent processes via formation of higher-order NP oligomers. Support for this unique mechanism is provided by site-directed mutagenesis studies, biophysical characterization of the oligomeric ligand:NP complex, and an X-ray cocrystal structure of an NP dimer of trimers (or hexamer) comprising three NP_A:NP_B dimeric subunits. Each NP_A:NP_B dimeric subunit contains two ligands that bridge two composite, protein-spanning binding sites in an antiparallel orientation to form a stable quaternary complex. Optimization of the initial screening hit produced an analog that protects mice from influenza-induced weight loss and mortality by reducing viral titers to undetectable levels throughout the course of treatment.
Asunto(s)
Antivirales/farmacología , Nucleoproteínas/química , Nucleoproteínas/metabolismo , Orthomyxoviridae/fisiología , Bibliotecas de Moléculas Pequeñas/farmacología , Replicación Viral/efectos de los fármacos , Animales , Antivirales/uso terapéutico , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Ensayos Analíticos de Alto Rendimiento , Hidrodinámica , Ratones , Modelos Moleculares , Nucleoproteínas/ultraestructura , Orthomyxoviridae/efectos de los fármacos , Infecciones por Orthomyxoviridae/tratamiento farmacológico , Infecciones por Orthomyxoviridae/virología , Multimerización de Proteína/efectos de los fármacos , Estructura Cuaternaria de Proteína , Bibliotecas de Moléculas Pequeñas/uso terapéutico , SolucionesRESUMEN
Several new potent CGRP receptor antagonists have been prepared in which the amide bond of lead compound 1 has been replaced by bioisosteric imidazole moieties. Substitution at N-1 of the imidazole was optimized to afford compounds with comparable potency to that of lead 1. Conformational restraint of the imidazole to form tetrahydroimidazo[1,5-a]pyrazine 43 gave substantially improved permeability.
Asunto(s)
Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Imidazoles/química , Quinolonas/química , Línea Celular Tumoral , Permeabilidad de la Membrana Celular/efectos de los fármacos , Humanos , Imidazoles/síntesis química , Imidazoles/farmacología , Microsomas/metabolismo , Unión Proteica , Quinolonas/síntesis química , Quinolonas/farmacología , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismo , Relación Estructura-ActividadRESUMEN
Various substituted indazole and benzoxazolone amino acids were investigated as d-tyrosine surrogates in highly potent CGRP receptor antagonists. Compound 3, derived from the 7-methylindazole core, afforded a 30-fold increase in CGRP binding potency compared with its unsubstituted indazole analog 1. When dosed at 0.03mg/kg SC, compound 2 (a racemic mixture of 3 and its (S)-enantiomer) demonstrated robust inhibition of CGRP-induced increases in mamoset facial blood flow up to 105min. The compound possesses a favorable predictive in vitro toxicology profile, and good aqueous solubility. When dosed as a nasal spray in rabbits, 3 was rapidly absorbed and showed good intranasal bioavailability (42%).
Asunto(s)
Aminoácidos/química , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Indazoles/síntesis química , Quinazolinonas/síntesis química , Tirosina/química , Administración Intranasal , Aminoácidos/síntesis química , Aminoácidos/farmacocinética , Animales , Benzoxazoles/química , Disponibilidad Biológica , Semivida , Indazoles/química , Indazoles/farmacocinética , Unión Proteica , Quinazolinonas/química , Quinazolinonas/farmacocinética , Conejos , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismo , Relación Estructura-ActividadRESUMEN
Calcitonin gene-related peptide (CGRP) receptor antagonists have been shown to be efficacious as abortive migraine therapeutics with the absence of cardiovascular liabilities that are associated with triptans. Herein, we report the discovery of a highly potent CGRP receptor antagonist, BMS-742413, with the potential to provide rapid onset of action through intranasal delivery. The compound displays excellent aqueous solubility, oxidative stability, and toxicological profile. BMS-742413 has good intranasal bioavailability in the rabbit and shows a robust, dose-dependent inhibition of CGRP-induced increases in marmoset facial blood flow.
Asunto(s)
Amidas/química , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Indazoles/química , Quinolonas/química , Administración Intranasal , Amidas/farmacología , Amidas/uso terapéutico , Animales , Células CACO-2 , Callithrix , Vasos Coronarios/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Cara/irrigación sanguínea , Humanos , Indazoles/farmacología , Indazoles/uso terapéutico , Trastornos Migrañosos/tratamiento farmacológico , Quinolonas/farmacología , Quinolonas/uso terapéutico , Conejos , Ratas , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismo , Mucosa Respiratoria/efectos de los fármacos , Mucosa Respiratoria/patologíaRESUMEN
We have systematically studied the effects of varying the central unnatural amino acid moiety on CGRP receptor antagonist potency and CYP inhibition in a series of ureidoamides. In this Letter, we report the discovery of compound 23, a potent CGRP receptor antagonist with only weak CYP3A4 inhibition. Unlike the triptans, compound 23 did not cause active constriction of ex vivo human cerebral arteries. At doses of 0.3-1 mg/kg (s.c.), 23 showed robust inhibition of CGRP-induced increases in marmoset facial blood flow, a validated migraine model. Ureidoamide 23 derives from a novel amino acid, 1H-indazol-5-yl substituted alanine as a tyrosine surrogate.
Asunto(s)
Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Animales , Callithrix , Vasos Coronarios/efectos de los fármacos , Inhibidores del Citocromo P-450 CYP3A , Humanos , Técnicas In Vitro , Estructura Molecular , Relación Estructura-Actividad , Tirosina/químicaRESUMEN
The calcitonin gene-related peptide (CGRP) receptor has been implicated in the pathogenesis of migraine. A class of urethanamide derivatives has been identified as potent inhibitors of the CGRP receptor. Compound 20 was found to be among the most potent (IC(50)=17pM). It was shown to retain excellent aqueous solubility (>50mg/mL, pH 7) while dramatically improving solution stability as compared to our previously disclosed development candidate, BMS-694153 (1).
Asunto(s)
Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Carbamatos/química , Indazoles/química , Quinazolinonas/química , Quinolonas/química , Carbamatos/síntesis química , Carbamatos/farmacología , Estabilidad de Medicamentos , Humanos , Trastornos Migrañosos/tratamiento farmacológico , Quinolonas/síntesis química , Quinolonas/farmacología , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismoRESUMEN
The thermodynamics underpinning cocrystal formation are derived. The results provide the pharmaceutical scientist with the foundation to experimentally assess the thermodynamic stability of a cocrystal with respect to its component forms. Data for the carbamazepine-nicotinamide system are discussed as an example.
Asunto(s)
Carbamazepina/química , Niacinamida/química , Termodinámica , Química Farmacéutica , Cristalización , Estabilidad de MedicamentosRESUMEN
The discovery of a back-up to the hepatitis C virus NS3 protease inhibitor asunaprevir (2) is described. The objective of this work was the identification of a drug with antiviral properties and toxicology parameters similar to 2, but with a preclinical pharmacokinetic (PK) profile that was predictive of once-daily dosing. Critical to this discovery process was the employment of an ex vivo cardiovascular (CV) model which served to identify compounds that, like 2, were free of the CV liabilities that resulted in the discontinuation of BMS-605339 (1) from clinical trials. Structure-activity relationships (SARs) at each of the structural subsites in 2 were explored with substantial improvement in PK through modifications at the P1 site, while potency gains were found with small, but rationally designed structural changes to P4. Additional modifications at P3 were required to optimize the CV profile, and these combined SARs led to the discovery of BMS-890068 (29).
Asunto(s)
Antivirales/química , Hepacivirus/efectos de los fármacos , Isoquinolinas/uso terapéutico , Oligopéptidos/química , Sulfonamidas/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/administración & dosificación , Antivirales/farmacocinética , Antivirales/farmacología , Perros , Esquema de Medicación , Farmacorresistencia Viral , Hepacivirus/genética , Macaca fascicularis , Masculino , Modelos Moleculares , Oligopéptidos/administración & dosificación , Oligopéptidos/farmacocinética , Oligopéptidos/farmacología , Conejos , Ratas Sprague-Dawley , Replicón , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/administración & dosificación , Sulfonamidas/farmacocinética , Sulfonamidas/farmacología , Sulfonamidas/uso terapéuticoRESUMEN
The discovery of asunaprevir (BMS-650032, 24) is described. This tripeptidic acylsulfonamide inhibitor of the NS3/4A enzyme is currently in phase III clinical trials for the treatment of hepatitis C virus infection. The discovery of 24 was enabled by employing an isolated rabbit heart model to screen for the cardiovascular (CV) liabilities (changes to HR and SNRT) that were responsible for the discontinuation of an earlier lead from this chemical series, BMS-605339 (1), from clinical trials. The structure-activity relationships (SARs) developed with respect to CV effects established that small structural changes to the P2* subsite of the molecule had a significant impact on the CV profile of a given compound. The antiviral activity, preclincial PK profile, and toxicology studies in rat and dog supported clinical development of BMS-650032 (24).
Asunto(s)
Antivirales/uso terapéutico , Hepatitis C/tratamiento farmacológico , Isoquinolinas/uso terapéutico , Inhibidores de Proteasas/uso terapéutico , Sulfonamidas/uso terapéutico , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/sangre , Antivirales/química , Perros , Humanos , Isoquinolinas/sangre , Isoquinolinas/química , Modelos Moleculares , Inhibidores de Proteasas/sangre , Inhibidores de Proteasas/química , Conejos , Ratas , Sulfonamidas/sangre , Sulfonamidas/químicaRESUMEN
Nanosuspensions of the example compounds ketoconazole and itraconazole were shown to aggregate upon reducing the pH to levels comparable to that known to exist in the stomach. Manipulation of the surfactant/polymer ratio in the suspension vehicle did not elucidate the cause of the aggregation. X-ray diffraction on ketoconazole solids failed to identify a form change as causative. Ultimately, ketoconazole intrinsic dissolution rate experiments implicated surface salt formation between ketoconazole and the vehicle surfactant as the cause of the aggregation. The generality of the phenomenon is discussed.
Asunto(s)
Ácido Dioctil Sulfosuccínico/química , Itraconazol/química , Cetoconazol/química , Nanopartículas/química , Povidona/química , Tensoactivos/química , Composición de Medicamentos , Estabilidad de Medicamentos , Furosemida/química , Concentración de Iones de Hidrógeno , Piroxicam/química , SuspensionesRESUMEN
Calcitonin gene-related peptide (CGRP) receptor antagonists have been clinically shown to be effective in the treatment of migraine, but identification of potent and orally bioavailable compounds has been challenging. Herein, we describe the conceptualization, synthesis, and preclinical characterization of a potent, orally active CGRP receptor antagonist 5 (BMS-846372). Compound 5 has good oral bioavailability in rat, dog, and cynomolgus monkeys and overall attractive preclinical properties including strong (>50% inhibition) exposure-dependent in vivo efficacy in a marmoset migraine model.
RESUMEN
Calcitonin gene-related peptide (CGRP) receptor antagonists have demonstrated clinical efficacy in the treatment of acute migraine. Herein, we describe the design, synthesis, and preclinical characterization of a highly potent, oral CGRP receptor antagonist BMS-927711 (8). Compound 8 has good oral bioavailability in rat and cynomolgus monkey, attractive overall preclinical properties, and shows dose-dependent activity in a primate model of CGRP-induced facial blood flow. Compound 8 is presently in phase II clinical trials.
Asunto(s)
Péptido Relacionado con Gen de Calcitonina/antagonistas & inhibidores , Descubrimiento de Drogas , Trastornos Migrañosos/tratamiento farmacológico , Piperidinas/química , Piperidinas/uso terapéutico , Piridinas/química , Piridinas/uso terapéutico , Administración Oral , Ensayos Clínicos como Asunto , Humanos , Espectroscopía de Resonancia Magnética , Piperidinas/farmacología , Piridinas/farmacologíaRESUMEN
Detailed metabolic characterization of 8, an earlier lead pyrazinone-based corticotropin-releasing factor-1 (CRF(1)) receptor antagonist, revealed that this compound formed significant levels of reactive metabolites, as measured by in vivo and in vitro biotransformation studies. This was of particular concern due to the body of evidence suggesting that reactive metabolites may be involved in idiosyncratic drug reactions. Further optimization of the structure-activity relationships and in vivo properties of pyrazinone-based CRF(1) receptor antagonists and studies to assess the formation of reactive metabolites led to the discovery of 19e, a high affinity CRF(1) receptor antagonist (IC(50) = 0.86 nM) wherein GSH adducts were estimated to be only 0.1% of the total amount of drug-related material excreted through bile and urine, indicating low levels of reactive metabolite formation in vivo. A novel 6-(difluoromethoxy)-2,5-dimethylpyridin-3-amine group in 19e contributed to the potency and improved in vivo properties of this compound and related analogues. 19e had excellent pharmacokinetic properties in rats and dogs and showed efficacy in the defensive withdrawal model of anxiety in rats. The lowest efficacious dose was 1.8 mg/kg. The results of a two-week rat safety study with 19e indicated that this compound was well-tolerated.
Asunto(s)
Pirazinas/metabolismo , Pirazinas/farmacología , Piridinas/metabolismo , Piridinas/farmacología , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Perros , Descubrimiento de Drogas , Estabilidad de Medicamentos , Humanos , Masculino , Pirazinas/administración & dosificación , Pirazinas/farmacocinética , Piridinas/administración & dosificación , Piridinas/farmacocinética , RatasRESUMEN
Calcitonin gene-related peptide (CGRP) has been implicated in the pathogenesis of migraine. Early chemistry leads suffered from modest potency, significant CYP3A4 inhibition, and poor aqueous solubility. Herein, we describe the optimization of these leads to give 4 (BMS-694153), a molecule with outstanding potency, a favorable predictive toxicology profile, and remarkable aqueous solubility. Compound 4 has good intranasal bioavailability in rabbits and shows dose-dependent activity in validated in vivo and ex vivo migraine models.