Identification of prostaglandin D2 receptor antagonists based on a tetrahydropyridoindole scaffold.
A new series of indole-based antagonists of the PGD(2) receptor subtype 1 (DP1 receptor) was identified and the progress of the structure-activity relationship study to the identification of potent and selective antagonists is presented. Selective DP1 antagonists with high potency and selectivity were prepared. Of particular interest is the DP1 antagonist 26 with a K(i) value of 1 nM for the DP1 receptor and an IC(50) value of 4.6 nM in a DP1 functional assay for the inhibition of the PGD(2) induced cAMP production in platelet rich plasma (PRP).
Beaulieu
Christian
C
Department of Medicinal Chemistry, Merck Frosst Canada & Co., 16711 Trans Canada Hwy, Kirkland, Que., Canada. christian_beaulieu@merck.com
Guay
Daniel
D
Wang
Zhaoyin
Z
Leblanc
Yves
Y
Roy
Patrick
P
Dufresne
Claude
C
Zamboni
Robert
R
Berthelette
Carl
C
Day
Stephen
S
Tsou
Nancy
N
Denis
Danielle
D
Greig
Gillian
G
Mathieu
Marie-Claude
MC
O'Neill
Gary
G
D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006859:Hydrogen / Q000737:chemistry*; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D011725:Pyridines / Q000737:chemistry*; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D007211:Indoles; D011725:Pyridines; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D006859:Hydrogen; C023666:pyridine; C036293:prostaglandin D2 receptor