(E)-Alkenes as replacements of amide bonds: development of novel and potent acyclic CGRP receptor antagonists

June J Kim; Michael R Wood; Shawn J Stachel; Pablo de Leon; Ashley Nomland; Craig A Stump; Melody A McWherter; Kathy M Schirripa; Eric L Moore; Christopher A Salvatore; Harold G Selnick

doi:10.1016/j.bmcl.2013.11.027

(E)-Alkenes as replacements of amide bonds: development of novel and potent acyclic CGRP receptor antagonists

Bioorg Med Chem Lett. 2014 Jan 1;24(1):258-61. doi: 10.1016/j.bmcl.2013.11.027. Epub 2013 Nov 20.

Affiliations

¹ Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States. Electronic address: june.kim@merck.com.
² Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
³ Department of Pain Research, Merck & Co., Inc., PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.

PMID: 24332093
DOI: 10.1016/j.bmcl.2013.11.027

Abstract

A new class of CGRP receptor antagonists was identified by replacing the central amide of a previously identified anilide lead structure with ethylene, ethane, or ethyne linkers. (E)-Alkenes as well as alkynes were found to preserve the proper bioactive conformation of the amides, necessary for efficient receptor binding. Further exploration resulted in several potent compounds against CGRP-R with low susceptibility to P-gp mediated efflux.

Keywords: (E)-Alkene; CGRP; Migraine; P-gp.

MeSH terms

Alkenes / chemical synthesis
Alkenes / chemistry
Alkenes / pharmacology*
Amides / chemistry
Calcitonin Gene-Related Peptide Receptor Antagonists*
Dose-Response Relationship, Drug
HEK293 Cells
Humans
Molecular Structure
Structure-Activity Relationship

Substances

Alkenes
Amides
Calcitonin Gene-Related Peptide Receptor Antagonists