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

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

Author information

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.

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

PMID:
24332093
DOI:
10.1016/j.bmcl.2013.11.027
[Indexed for MEDLINE]

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