Novel oxazolidinone calcitonin gene-related peptide (CGRP) receptor antagonists for the acute treatment of migraine

Autor:	Amy G. Quigley, Daniel V. Paone, Melody Mcwherter, Andrew Danziger, Brendan M. Crowley, Mark E. Fraley, Danny Gauvreau, Dan Cui, Karsten Menzel, J. Christopher Culberson, Joseph G. Bruno, Vijay Bhasker G. Reddy, Christopher A. Salvatore, Ian M. Bell, Craig A. Stump, Christopher S. Burgey, Eric L. Moore, Stefanie A. Kane, Amanda L. Kemmerer, Scott D. Mosser, Christine Fandozzi, Diem N. Nguyen, Craig M. Potteiger, Harold G. Selnick, Rebecca B. White
Rok vydání:	2015
Předmět:	Migraine Disorders Clinical Biochemistry hERG Pharmaceutical Science Pharmacology Calcitonin gene-related peptide Biochemistry Structure-Activity Relationship Pharmacokinetics Calcitonin Gene-Related Peptide Receptor Antagonists Drug Discovery medicine Potency Structure–activity relationship Animals Humans Molecular Biology IC50 CGRP receptor Oxazolidinones biology Dose-Response Relationship Drug Molecular Structure Chemistry Organic Chemistry medicine.disease Rats Molecular Docking Simulation Migraine biology.protein Molecular Medicine
Zdroj:	Bioorganicmedicinal chemistry letters. 25(21)
ISSN:	1464-3405
Popis:	In our efforts to develop CGRP receptor antagonists as backups to MK-3207, 2, we employed a scaffold hopping approach to identify a series of novel oxazolidinone-based compounds. The development of a structurally diverse, potent (20, cAMP+HS IC50=0.67 nM), and selective compound (hERG IC50=19 μM) with favorable rodent pharmacokinetics (F=100%, t1/2=7h) is described. Key to this development was identification of a 3-substituted spirotetrahydropyran ring that afforded a substantial gain in potency (10 to 35-fold).
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::daf3aa4e8fe72f15e10763373e410d9a https://pubmed.ncbi.nlm.nih.gov/26231160 Zobrazit plný text záznamu Full Text from ScienceDirect