title: Discovery of (R)-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 (BMS-694153): a potent antagonist of the human calcitonin gene-related peptide receptor for migraine with rapid and efficient intranasal exposure.
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.
authors.affiliation: Department of Neuroscience Chemistry, Bristol-Myers Squibb Research & Development,Wallingford, Connecticut 06492, USA. andrew.degnan@bms.com
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Degnan
authors.forename: Prasad V
authors.initials: PV
authors.lastname: Chaturvedula
authors.forename: Charles M
authors.initials: CM
authors.lastname: Conway
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Cook
authors.forename: Carl D
authors.initials: CD
authors.lastname: Davis
authors.forename: Rex
authors.initials: R
authors.lastname: Denton
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Han
authors.forename: Robert
authors.initials: R
authors.lastname: Macci
authors.forename: Neil R
authors.initials: NR
authors.lastname: Mathias
authors.forename: Paul
authors.initials: P
authors.lastname: Moench
authors.forename: Sokhom S
authors.initials: SS
authors.lastname: Pin
authors.forename: Shelly X
authors.initials: SX
authors.lastname: Ren
authors.forename: Richard
authors.initials: R
authors.lastname: Schartman
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Signor
authors.forename: George
authors.initials: G
authors.lastname: Thalody
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Widmann
authors.forename: Cen
authors.initials: C
authors.lastname: Xu
authors.forename: John E
authors.initials: JE
authors.lastname: Macor
authors.forename: Gene M
authors.initials: GM
authors.lastname: Dubowchik
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001682:Biological Availability; D015740:Calcitonin Gene-Related Peptide / Q000037:antagonists & inhibitors; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002144:Callithrix; D003331:Coronary Vessels / Q000187:drug effects; D005145:Face / Q000098:blood supply; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use*; D008881:Migraine Disorders / Q000188:drug therapy*; D052999:Quinazolinones / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use*; D011817:Rabbits; D012039:Regional Blood Flow / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: C531228:4-(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; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D007191:Indazoles; D052999:Quinazolinones; D015740:Calcitonin Gene-Related Peptide