title: Discovery of (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)-1-oxopropan-2-yl)-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide (BMS-742413): a potent human CGRP antagonist with superior safety profile for the treatment of migraine through intranasal delivery.
abstract: 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.
authors: Department of Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb R&D, 5 Research Parkway, Wallingford, CT 06492, USA. Prasad.Chaturvedula@bms.com
authors: Prasad V
authors: PV
authors: Chaturvedula
authors: Stephen E
authors: SE
authors: Mercer
authors: Sokhom S
authors: SS
authors: Pin
authors: George
authors: G
authors: Thalody
authors: Cen
authors: C
authors: Xu
authors: Charlie M
authors: CM
authors: Conway
authors: Deborah
authors: D
authors: Keavy
authors: Laura
authors: L
authors: Signor
authors: Glenn H
authors: GH
authors: Cantor
authors: Neil
authors: N
authors: Mathias
authors: Paul
authors: P
authors: Moench
authors: Rex
authors: R
authors: Denton
authors: Robert
authors: R
authors: Macci
authors: Richard
authors: R
authors: Schartman
authors: Valerie
authors: V
authors: Whiterock
authors: Carl
authors: C
authors: Davis
authors: John E
authors: JE
authors: Macor
authors: Gene M
authors: GM
authors: Dubowchik
mesh_terms: D000281:Administration, Intranasal; D000577:Amides / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D018938:Caco-2 Cells; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002144:Callithrix; D003331:Coronary Vessels / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D005145:Face / Q000098:blood supply; D006801:Humans; D007191:Indazoles / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D008881:Migraine Disorders / Q000188:drug therapy; D015363:Quinolones / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D011817:Rabbits; D051381:Rats; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects / Q000473:pathology
chemical_list: D000577:Amides; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D007191:Indazoles; C584752:N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)-1-oxopropan-2-yl))-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide; D015363:Quinolones; D018015:Receptors, Calcitonin Gene-Related Peptide