title: [(1H-imidazol-1-yl)methyl]- and [(3-pyridinyl)methyl]pyrroles as thromboxane synthetase inhibitors.
abstract: Several [(1H-imidazol-1-yl)methyl]- and [(3-pyridinyl)methyl] pyrroles were prepared and evaluated in vitro as thromboxane synthetase inhibitors in human platelet aggregation studies. A number of structures, e.g. 10b,f,g,i (respective IC50 values: 1 microM, 50 nM, 42 nM, 44 nM) showed superior in vitro inhibition of TXA2 synthetase when compared to the standard dazoxiben (1). However, it was found that in vitro potency did not translate into nor correlate with in vivo activity when these compounds were evaluated in mice in a collagen-epinephrine-induced pulmonary thromboembolism model. (E)-1-Methyl-2-[(1H-imidazol-1-yl)methyl]-5-(2-carboxyprop-1-enyl) pyrrole (10b) was found to offer protection against collagen-epinephrine-induced mortality in mice, thereby demonstrating that oral administration is an effective route for absorption of this drug. Additional evidence for the oral effectiveness of 10b in lowering serum TXB2 levels was obtained by performing ex vivo radioimmunoassay experiments with rats. A 13-week study of 10b in rats with reduced renal mass was conducted in order to evaluate the role of TXA2 production in hypertension and renal dysfunction. Although serum and urinary TXB2 levels in rats were found to be lowered during this study by 10b, the levels of urinary protein excretion remained comparable to that of the control group.
authors.affiliation: Institute of Organic Chemistry, Syntex Research, Palo Alto, California 94304.
authors.forename: G R
authors.initials: GR
authors.lastname: Martinez
authors.forename: K A
authors.initials: KA
authors.lastname: Walker
authors.forename: D R
authors.initials: DR
authors.lastname: Hirschfeld
authors.forename: P J
authors.initials: PJ
authors.lastname: Maloney
authors.forename: D S
authors.initials: DS
authors.lastname: Yang
authors.forename: R P
authors.initials: RP
authors.lastname: Rosenkranz
mesh_terms: D000818:Animals; D001011:Aorta / Q000648:ultrastructure; D001682:Biological Availability; D001792:Blood Platelets / Q000201:enzymology; D055598:Chemical Phenomena; D002621:Chemistry; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D007249:Inflammation / Q000201:enzymology; D007674:Kidney Diseases / Q000378:metabolism; D008297:Male; D051379:Mice; D008861:Microsomes / Q000201:enzymology; D010975:Platelet Aggregation Inhibitors; D011450:Prostaglandin Endoperoxides, Synthetic / Q000097:blood; D044262:Prostaglandin H2; D011463:Prostaglandins H / Q000097:blood; D011725:Pyridines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013552:Swine; D013928:Thromboxane A2 / Q000097:blood / Q000378:metabolism; D013929:Thromboxane B2 / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
chemical_list: D007093:Imidazoles; D010975:Platelet Aggregation Inhibitors; D011450:Prostaglandin Endoperoxides, Synthetic; D011463:Prostaglandins H; D011725:Pyridines; D011758:Pyrroles; D044262:Prostaglandin H2; D013929:Thromboxane B2; D013928:Thromboxane A2; D013930:Thromboxane-A Synthase