Novel CGRP receptor antagonists through a design strategy of target simplification with addition of molecular flexibility.
A novel class of CGRP receptor antagonists was rationally designed by modifying a highly potent, but structurally complex, CGRP receptor antagonist. Initial modifications focused on simplified structures, with increased flexibility. Subsequent to the preparation of a less-potent but more flexible lead, classic medicinal chemistry methods were applied to restore high affinity (compound 22, CGRP Ki=0.035 nM) while maintaining structural diversity relative to the lead. Good selectivity against the closely related adrenomedullin-2 receptor was also achieved.
Wood
Michael R
MR
Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, USA.
Schirripa
Kathy M
KM
Kim
June J
JJ
Quigley
Amy G
AG
Stump
Craig A
CA
Bell
Ian M
IM
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
Kane
Stefanie A
SA
Vacca
Joseph P
JP
Selnick
Harold G
HG
D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002460:Cell Line; D015195:Drug Design; D006801:Humans; D051381:Rats; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000378:metabolism; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000081:Acetamides; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D018015:Receptors, Calcitonin Gene-Related Peptide; D013141:Spiro Compounds