title: (E)-Alkenes as replacements of amide bonds: development of novel and potent acyclic CGRP receptor antagonists.
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.
authors: 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.
authors: June J
authors: JJ
authors: Kim
authors: Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
authors: Michael R
authors: MR
authors: Wood
authors: Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
authors: Shawn J
authors: SJ
authors: Stachel
authors: Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
authors: Pablo
authors: P
authors: de Leon
authors: Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
authors: Ashley
authors: A
authors: Nomland
authors: Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
authors: Craig A
authors: CA
authors: Stump
authors: Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
authors: Melody A
authors: MA
authors: McWherter
authors: Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
authors: Kathy M
authors: KM
authors: Schirripa
authors: Department of Pain Research, Merck & Co., Inc., PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
authors: Eric L
authors: EL
authors: Moore
authors: Department of Pain Research, Merck & Co., Inc., PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
authors: Christopher A
authors: CA
authors: Salvatore
authors: Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
authors: Harold G
authors: HG
authors: Selnick
mesh_terms: D000475:Alkenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000577:Amides / Q000737:chemistry; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000475:Alkenes; D000577:Amides; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists
keywords: (E)-Alkene; CGRP; Migraine; P-gp