The discovery of highly potent CGRP receptor antagonists.
Rational modification of a previously identified spirohydantoin lead structure has identified a series of potent spiroazaoxindole CGRP receptor antagonists. The azaoxindole was found to be a general replacement for the hydantoin that consistently improved in vitro potency. The combination of the indanylspiroazaoxindole and optimized benzimidazolinones led to highly potent antagonists (e.g., 25, CGRP K(i)=40pM). The closely related compound 27 demonstrated good oral bioavailability in dog and rhesus.
Stump
Craig A
CA
Department of Medicinal Chemistry, Merck & Co, Inc, West Point, PA 19486, USA. craig_stump@merck.com
Bell
Ian M
IM
Bednar
Rodney A
RA
Bruno
Joseph G
JG
Fay
John F
JF
Gallicchio
Steven N
SN
Johnston
Victor K
VK
Moore
Eric L
EL
Mosser
Scott D
SD
Quigley
Amy G
AG
Salvatore
Christopher A
CA
Theberge
Cory R
CR
Blair Zartman
C
C
Zhang
Xu-Fang
XF
Kane
Stefanie A
SA
Graham
Samuel L
SL
Vacca
Joseph P
JP
Williams
Theresa M
TM
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D004285:Dogs; D055808:Drug Discovery; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D008253:Macaca mulatta; D000078183:Oxindoles; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D007211:Indoles; D000078183:Oxindoles; D013141:Spiro Compounds; C022960:2-oxindole