title: Synthesis and SAR of calcitonin gene-related peptide (CGRP) antagonists containing substituted aryl-piperazines and piperidines.
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.
authors.affiliation: Bristol-Myers Squibb Discovery, Bristol-Myers Squibb Research & Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Rita L
authors.initials: RL
authors.lastname: Civiello
authors.affiliation: Bristol-Myers Squibb Discovery, Bristol-Myers Squibb Research & Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Han
authors.affiliation: Bristol-Myers Squibb Discovery, Bristol-Myers Squibb Research & Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Brett R
authors.initials: BR
authors.lastname: Beno
authors.affiliation: Bristol-Myers Squibb Discovery, Bristol-Myers Squibb Research & Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Prasad V
authors.initials: PV
authors.lastname: Chaturvedula
authors.affiliation: Bristol-Myers Squibb Discovery, Bristol-Myers Squibb Research & Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Herbst
authors.affiliation: Bristol-Myers Squibb Discovery, Bristol-Myers Squibb Research & Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Cen
authors.initials: C
authors.lastname: Xu
authors.affiliation: Bristol-Myers Squibb Discovery, Bristol-Myers Squibb Research & Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Conway
authors.affiliation: Bristol-Myers Squibb Discovery, Bristol-Myers Squibb Research & Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Macor
authors.affiliation: Bristol-Myers Squibb Discovery, Bristol-Myers Squibb Research & Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Gene M
authors.initials: GM
authors.lastname: Dubowchik
mesh_terms: D015740:Calcitonin Gene-Related Peptide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry*; D010880:Piperidines / Q000737:chemistry*; D052999:Quinazolinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
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; D007191:Indazoles; D010879:Piperazines; D010880:Piperidines; D052999:Quinazolinones; D000077489:Piperazine; C032727:piperidine; D015740:Calcitonin Gene-Related Peptide
keywords: CGRP receptor antagonist; Calcitonin gene-related peptide (CGRP); Migraine headache