Abstract
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.
Keywords:
CGRP receptor antagonist; Calcitonin gene-related peptide (CGRP); Migraine headache.
Copyright © 2016 Elsevier Ltd. All rights reserved.
MeSH terms
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Calcitonin Gene-Related Peptide / antagonists & inhibitors*
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Calcitonin Gene-Related Peptide / metabolism
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Cell Line, Tumor
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Cell Membrane Permeability / drug effects
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Humans
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Indazoles / chemical synthesis
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Indazoles / chemistry*
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Indazoles / pharmacology
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Inhibitory Concentration 50
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Piperazine
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Piperazines / chemistry*
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Piperidines / chemistry*
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Quinazolinones / chemical synthesis
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Quinazolinones / chemistry*
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Quinazolinones / pharmacology
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Structure-Activity Relationship
Substances
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4-(8-fluoro-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl)propan-2-yl)piperidine-1-carboxamide
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Indazoles
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Piperazines
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Piperidines
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Quinazolinones
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Piperazine
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piperidine
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Calcitonin Gene-Related Peptide