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

Brendan M Crowley; Craig A Stump; Diem N Nguyen; Craig M Potteiger; Melody A McWherter; Daniel V Paone; Amy G Quigley; Joseph G Bruno; Dan Cui; J Christopher Culberson; Andrew Danziger; Christine Fandozzi; Danny Gauvreau; Amanda L Kemmerer; Karsten Menzel; Eric L Moore; Scott D Mosser; Vijay Reddy; Rebecca B White; Christopher A Salvatore; Stefanie A Kane; Ian M Bell; Harold G Selnick; Mark E Fraley; Christopher S Burgey

doi:10.1016/j.bmcl.2015.07.021

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

Bioorg Med Chem Lett. 2015 Nov 1;25(21):4777-4781. doi: 10.1016/j.bmcl.2015.07.021. Epub 2015 Jul 14.

Authors

Brendan M Crowley¹, Craig A Stump², Diem N Nguyen², Craig M Potteiger², Melody A McWherter², Daniel V Paone², Amy G Quigley², Joseph G Bruno³, Dan Cui⁴, J Christopher Culberson⁵, Andrew Danziger⁶, Christine Fandozzi⁴, Danny Gauvreau⁷, Amanda L Kemmerer³, Karsten Menzel⁴, Eric L Moore⁸, Scott D Mosser³, Vijay Reddy⁹, Rebecca B White⁴, Christopher A Salvatore⁸, Stefanie A Kane⁸, Ian M Bell², Harold G Selnick², Mark E Fraley², Christopher S Burgey²

Affiliations

¹ Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 4, WP14-2, 770 Sumneytown Pike, West Point, PA 19486, USA. Electronic address: brendan_crowley@merck.com.
² Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 4, WP14-2, 770 Sumneytown Pike, West Point, PA 19486, USA.
³ Department of In Vitro Pharmacology, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
⁴ Department of Pharmacokinetics Pharmacodynamics & Drug Metabolism, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
⁵ Department of Chemistry Modeling and Informatics, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
⁶ Department of In Vivo Pharmacology, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
⁷ Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada.
⁸ Department of Pain & Migraine, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
⁹ Department of Genetic Tox & Molecular Carcinogenesis, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.

PMID: 26231160
DOI: 10.1016/j.bmcl.2015.07.021

Abstract

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).

Keywords: CGRP; Class B GPCR; Migraine; Oxazolidinone; Scaffold hopping.

MeSH terms

Animals
Calcitonin Gene-Related Peptide Receptor Antagonists*
Dose-Response Relationship, Drug
Humans
Migraine Disorders / drug therapy*
Molecular Docking Simulation
Molecular Structure
Oxazolidinones / chemical synthesis
Oxazolidinones / chemistry
Oxazolidinones / pharmacology*
Oxazolidinones / therapeutic use*
Rats
Structure-Activity Relationship

Substances

Calcitonin Gene-Related Peptide Receptor Antagonists
Oxazolidinones