Abstract
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.
MeSH terms
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Administration, Intranasal
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Animals
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Biological Availability
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Calcitonin Gene-Related Peptide / antagonists & inhibitors
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Calcitonin Gene-Related Peptide Receptor Antagonists*
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Callithrix
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Coronary Vessels / drug effects
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Face / blood supply
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Humans
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Indazoles / administration & dosage
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Indazoles / chemical synthesis
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Indazoles / therapeutic use*
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Migraine Disorders / drug therapy*
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Quinazolinones / administration & dosage
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Quinazolinones / chemical synthesis
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Quinazolinones / therapeutic use*
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Rabbits
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Regional Blood Flow / drug effects
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Vasodilation / drug effects
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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Calcitonin Gene-Related Peptide Receptor Antagonists
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Indazoles
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Quinazolinones
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Calcitonin Gene-Related Peptide