Structure-activity relationships associated with 3,4,5-triphenyl-1H-pyrazole-1-nonanoic acid, a nonprostanoid prostacyclin mimetic.
A series of phenylated pyrazoloalkanoic acid derivatives were synthesized and evaluated as inhibitors of ADP-induced human platelet aggregation. 3,4,5-Triphenyl-1H-pyrazole-1-nonanoic acid (8d), with an IC50 of 0.4 microM, was the most potent inhibitor identified in this study. Biochemical studies determined that 8d increased intraplatelet cAMP accumulation and stimulated platelet membrane-bound adenylate cyclase in a concentration-dependent fashion. Displacement of [3H]iloprost by 8d from platelet membranes indicated that the platelet prostacyclin (PGI2) receptor is the locus of biological action. Structure-activity studies demonstrated that the minimum structural requirements for binding to the platelet PGI2 receptor and inhibition of ADP-induced platelet aggregation within this series are a vicinally diphenylated pyrazole substituted with an omega-alkanoic acid side chain eight or nine atoms long. Potency depended upon both side-chain length and its topological relationship with the two phenyl rings.
Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492.
N A
NA
Meanwell
M J
MJ
Rosenfeld
J J
JJ
Wright
C L
CL
Brassard
J O
JO
Buchanan
M E
ME
Federici
J S
JS
Fleming
S M
SM
Seiler
D000262:Adenylyl Cyclases / Q000097:blood / Q000187:drug effects; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D011464:Epoprostenol / Q000494:pharmacology*; D006801:Humans; D016285:Iloprost / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin / Q000187:drug effects*; D013329:Structure-Activity Relationship
D007093:Imidazoles; D010975:Platelet Aggregation Inhibitors; D011720:Pyrazoles; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin; C072408:3,4,5-triphenyl-1H-pyrazole-1-nonanoic acid; D011464:Epoprostenol; D000262:Adenylyl Cyclases; D016285:Iloprost; C054659:octimibate