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.
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.
Degnan
Andrew P
AP
Department of Neuroscience Chemistry, Bristol-Myers Squibb Research & Development,Wallingford, Connecticut 06492, USA. andrew.degnan@bms.com
Chaturvedula
Prasad V
PV
Conway
Charles M
CM
Cook
Deborah A
DA
Davis
Carl D
CD
Denton
Rex
R
Han
Xiaojun
X
Macci
Robert
R
Mathias
Neil R
NR
Moench
Paul
P
Pin
Sokhom S
SS
Ren
Shelly X
SX
Schartman
Richard
R
Signor
Laura J
LJ
Thalody
George
G
Widmann
Kimberly A
KA
Xu
Cen
C
Macor
John E
JE
Dubowchik
Gene M
GM
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
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