Identification of an indole series of prostaglandin D2 receptor antagonists.
A novel indole series of PGD2 receptor (DP receptor) antagonists is presented. Optimization of this series led to the identification of potent and selective DP receptor antagonists. In particular, antagonists 35 and 36 were identified with Ki values of 2.6 and 1.8 nM, respectively. These two antagonists are also potent in a DP functional assay where they inhibit the PGD2 induced cAMP production in platelet rich plasma with IC50 values of 7.9 and 8.6 nM, respectively. The structure-activity relationships of this indole series of DP receptor antagonists will also be discussed.
Sturino
Claudio F
CF
Department of Medicinal Chemistry, Merck Frosst Canada & Co., 16711 Trans Canada Hwy. Kirkland, Que., Canada H9H 3L1. claudio_sturino@merck.com
Lachance
Nicolas
N
Boyd
Michael
M
Berthelette
Carl
C
Labelle
Marc
M
Li
Lianhai
L
Roy
Bruno
B
Scheigetz
John
J
Tsou
Nancy
N
Brideau
Christine
C
Cauchon
Elizabeth
E
Carriere
Marie-Claude
MC
Denis
Danielle
D
Greig
Gillian
G
Kargman
Stacia
S
Lamontagne
Sonia
S
Mathieu
Marie-Claude
MC
Sawyer
Nicole
N
Slipetz
Deborah
D
O'Neill
Gary
G
Wang
Zhaoyin
Z
Zamboni
Robert
R
Metters
Kathleen M
KM
Young
Robert N
RN
D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015394:Molecular Structure; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012451:Safrole / Q000031:analogs & derivatives / Q000737:chemistry; D013329:Structure-Activity Relationship
D007211:Indoles; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; C030374:indole; D012451:Safrole; C005746:sulfoxide; C036293:prostaglandin D2 receptor