RESUMEN
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
Calcitonin gene-related peptide (CGRP) is a potent neuropeptide implicated in the pathophysiology of migraine. In the course of seeking CGRP antagonists with improved oral bioavailability, metabolic stability, and pharmacokinetic properties, lower molecular weight, structurally simpler piperidine and piperazine analogs of BMS-694153 were prepared. Several were found to have nM binding affinity in vitro. The synthesis and SAR of these substituted piperidine and piperazine CGRP antagonists are discussed.
Asunto(s)
Péptido Relacionado con Gen de Calcitonina/antagonistas & inhibidores , Indazoles/química , Piperazinas/química , Piperidinas/química , Quinazolinonas/química , Péptido Relacionado con Gen de Calcitonina/metabolismo , Línea Celular Tumoral , Permeabilidad de la Membrana Celular/efectos de los fármacos , Humanos , Indazoles/síntesis química , Indazoles/farmacología , Concentración 50 Inhibidora , Piperazina , Quinazolinonas/síntesis química , Quinazolinonas/farmacología , 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 report the synthesis of rigid spirocyclic systems as conformationally constrained variants of the Ala-Phe-NH(2) dipeptide amide C-terminus of the calcitonin gene-related peptide (CGRP). CGRP receptor antagonists containing these moieties displayed potent affinity, functional antagonism and excellent oxidative stability. Structure-activity relationship studies demonstrated the relative importance of hydrogen bond donor/acceptor functionalities and the preferred orientation of an aromatic ring. Antagonists showed potent and full reversal of CGRP-induced dilation of ex vivo human intracranial arteries.
Asunto(s)
Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Compuestos de Espiro/química , Diseño de Fármacos , Enlace de Hidrógeno , Estructura Molecular , Compuestos de Espiro/farmacología , Relación Estructura-ActividadRESUMEN
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
Herein we report the first room temperature Heck reaction of aryl bromides and CH(2)=C(NHP)CO(2)Me (P = Boc or CBz) to form ArCH=C(NHP)CO(2)Me, which are then used for the asymmetric syntheses of alpha-amino acids. We also report the first syntheses of ArCH=C(OCOAr(1))CO(2)Me (Ar(1) = Ph, 4-Cl-Ph) from ArBr and CH(2)=C(OCOAr(1))CO(2)Me by the Heck reaction and subsequent successful asymmetric hydrogenation to afford alpha-hydroxyl esters in excellent chemical yields and good-to-excellent enantioselectivities.
Asunto(s)
Aminoácidos/síntesis química , Hidróxidos/química , Aminoácidos/química , Bromuros/química , Catálisis , Ésteres/síntesis química , Ésteres/química , Estereoisomerismo , Especificidad por Sustrato , TemperaturaRESUMEN
Amino acid esters 5-11 as tyrosine mimics have been synthesized in excellent enantioselectivity (up to 99.6% ee) and in good overall chemical yields. The key step in the sequence was the Burk's [Rh(COD)(2R,5R)-Et-DuPhos]BF4-catalyzed asymmetric hydrogenation of enamides with a variety of reactive functional groups.
Asunto(s)
Ésteres/síntesis química , Imitación Molecular , Tirosina/química , Aminoácidos/química , Catálisis , Hidrogenación , EstereoisomerismoRESUMEN
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.