The identification of potent, orally bioavailable tricyclic CGRP receptor antagonists.
A series of tricyclic CGRP receptor antagonists was optimized in order to improve oral bioavailability. Attenuation of polar surface area and incorporation of a weakly basic indoline nitrogen led to compound 5, a potent antagonist with good oral bioavailability in three species.
Bell
Ian M
IM
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. ian_bell@merck.com
Bednar
Rodney A
RA
Corcoran
Halea A
HA
Fay
John F
JF
Gallicchio
Steven N
SN
Johnston
Victor K
VK
Hershey
James C
JC
Miller-Stein
Cynthia M
CM
Moore
Eric L
EL
Mosser
Scott D
SD
Roller
Shane A
SA
Salvatore
Christopher A
CA
Theberge
Cory R
CR
Wong
Bradley K
BK
Blair Zartman
C
C
Kane
Stefanie A
SA
Williams
Theresa M
TM
Graham
Samuel L
SL
Vacca
Joseph P
JP
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002460:Cell Line; D004285:Dogs; D000882:Haplorhini; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D051381:Rats; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000378:metabolism; D013141:Spiro Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*
D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D006575:Heterocyclic Compounds, 3-Ring; D018015:Receptors, Calcitonin Gene-Related Peptide; D013141:Spiro Compounds