Novel CGRP receptor antagonists from central amide replacements causing a reversal of preferred chirality.
A previously utilized quinoline-for-N-phenylamide replacement strategy was employed against a central amide in a novel class of CGRP receptor antagonists. A unique and unexpected substitution pattern was ultimately required to maintain reasonable affinity for the CGRP receptor, while at the same time predicting acceptable heterocycle positioning for related analogs. Subsequently, specific quinoline and naphthyridine compounds were prepared which supported these structural predictions by displaying CGRP binding affinities in the 0.037-0.15 nM range.
Wood
Michael R
MR
Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
Schirripa
Kathy M
KM
Kim
June J
JJ
Bednar
Rodney A
RA
Fay
John F
JF
Bruno
Joseph G
JG
Moore
Eric L
EL
Mosser
Scott D
SD
Roller
Shane
S
Salvatore
Christopher A
CA
Vacca
Joseph P
JP
Selnick
Harold G
HG
D000577:Amides / Q000737:chemistry / Q000494:pharmacology*; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D013237:Stereoisomerism
D000577:Amides; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists