ABSTRACT
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%).
Subject(s)
Azepines/pharmacology , Calcitonin Gene-Related Peptide Receptor Antagonists/pharmacology , Indazoles/pharmacology , Receptors, Calcitonin Gene-Related Peptide/metabolism , Azepines/chemistry , Calcitonin Gene-Related Peptide Receptor Antagonists/chemistry , Dose-Response Relationship, Drug , Humans , Indazoles/chemistry , Molecular Structure , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Calcitonin Gene-Related Peptide/antagonists & inhibitors , Indazoles/chemistry , Piperazines/chemistry , Piperidines/chemistry , Quinazolinones/chemistry , Calcitonin Gene-Related Peptide/metabolism , Cell Line, Tumor , Cell Membrane Permeability/drug effects , Humans , Indazoles/chemical synthesis , Indazoles/pharmacology , Inhibitory Concentration 50 , Piperazine , Quinazolinones/chemical synthesis , Quinazolinones/pharmacology , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Amides/chemistry , Calcitonin Gene-Related Peptide Receptor Antagonists , Indazoles/chemistry , Quinolones/chemistry , Administration, Intranasal , Amides/pharmacology , Amides/therapeutic use , Animals , Caco-2 Cells , Callithrix , Coronary Vessels/drug effects , Drug Evaluation, Preclinical , Face/blood supply , Humans , Indazoles/pharmacology , Indazoles/therapeutic use , Migraine Disorders/drug therapy , Quinolones/pharmacology , Quinolones/therapeutic use , Rabbits , Rats , Receptors, Calcitonin Gene-Related Peptide/metabolism , Respiratory Mucosa/drug effects , Respiratory Mucosa/pathologyABSTRACT
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.
Subject(s)
Calcitonin Gene-Related Peptide Receptor Antagonists , Animals , Callithrix , Coronary Vessels/drug effects , Cytochrome P-450 CYP3A Inhibitors , Humans , In Vitro Techniques , Molecular Structure , Structure-Activity Relationship , Tyrosine/chemistryABSTRACT
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.
Subject(s)
Calcitonin Gene-Related Peptide Receptor Antagonists , Spiro Compounds/chemistry , Drug Design , Hydrogen Bonding , Molecular Structure , Spiro Compounds/pharmacology , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Amino Acids/chemical synthesis , Hydroxides/chemistry , Amino Acids/chemistry , Bromides/chemistry , Catalysis , Esters/chemical synthesis , Esters/chemistry , Stereoisomerism , Substrate Specificity , TemperatureABSTRACT
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.
Subject(s)
Esters/chemical synthesis , Molecular Mimicry , Tyrosine/chemistry , Amino Acids/chemistry , Catalysis , Hydrogenation , StereoisomerismABSTRACT
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.