RÉSUMÉ
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.
Sujet(s)
Azépines/pharmacologie , Antagonistes du récepteur du peptide relié au gène de la calcitonine/pharmacologie , Récepteurs du peptide relié au gène de la calcitonine/métabolisme , Azépines/synthèse chimique , Azépines/composition chimique , Antagonistes du récepteur du peptide relié au gène de la calcitonine/synthèse chimique , Antagonistes du récepteur du peptide relié au gène de la calcitonine/composition chimique , Relation dose-effet des médicaments , Humains , Structure moléculaire , Relation structure-activitéRÉSUMÉ
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%).
Sujet(s)
Azépines/pharmacologie , Antagonistes du récepteur du peptide relié au gène de la calcitonine/pharmacologie , Indazoles/pharmacologie , Récepteurs du peptide relié au gène de la calcitonine/métabolisme , Azépines/composition chimique , Antagonistes du récepteur du peptide relié au gène de la calcitonine/composition chimique , Relation dose-effet des médicaments , Humains , Indazoles/composition chimique , Structure moléculaire , Relation structure-activitéRÉSUMÉ
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.
Sujet(s)
Antagonistes du récepteur du peptide relié au gène de la calcitonine , Imidazoles/composition chimique , Quinolinone/composition chimique , Lignée cellulaire tumorale , Perméabilité des membranes cellulaires/effets des médicaments et des substances chimiques , Humains , Imidazoles/synthèse chimique , Imidazoles/pharmacologie , Microsomes/métabolisme , Liaison aux protéines , Quinolinone/synthèse chimique , Quinolinone/pharmacologie , Récepteurs du peptide relié au gène de la calcitonine/métabolisme , Relation structure-activitéRÉSUMÉ
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.
Sujet(s)
Antagonistes du récepteur du peptide relié au gène de la calcitonine , Animaux , Callithrix , Vaisseaux coronaires/effets des médicaments et des substances chimiques , Inhibiteurs du cytochrome P-450 CYP3A , Humains , Techniques in vitro , Structure moléculaire , Relation structure-activité , Tyrosine/composition chimiqueRÉSUMÉ
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.