Thromboxane synthase inhibitors and thromboxane A2 receptor antagonists: a quantitative structure activity relationships (QSARs) analysis.
Thromboxane A(2) (TxA(2)), a bioactive metabolite of the Arachidonic acid (AA), is a potent mediator of platelet aggregation, vasoconstriction and bronchoconstriction. It plays an important role in major human diseases, such as myocardial infraction, unstable angina, pregnancy-induced hypertension and preeclampsia, thrombosis and thrombotic disorders, pulmonary hypertension, asthma, septic shock, atherosclerosis, lupus nephritis, and Raynaud's phenomenon. Thus, TxA(2) is a therapeutic target for many research groups. A number of TXA(2) receptor antagonists as well as thromboxane synthase inhibitors have been developed. In this research we review and evaluate new quantitative structure activity relationships of thromboxane synthase inhibitors and thromboxane receptor antagonists, using the C-QSAR program of Biobyte. Lipophicity, as Clog P is a significant physicochemical parameter for this biological response. CMR/MR molar refractivity as well as sterimol parameters seemed to be important as well Molecular Volume. Electronic effects with the exception of σ Hammett's constant are not found to govern the biological activity. The derived equations will be very helpful for the design of new potent molecules.
Kontogiorgis
C
C
Aristotle University of Thessaloniki, School of Pharmacy, Department of Pharmaceutical Chemistry, Thessaloniki, Greece. kontog@pharm.auth.gr
Hadjipavlou-Litina
D
D
D016718:Arachidonic Acid / Q000378:metabolism; D052176:Azulenes / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D052176:Azulenes; D004791:Enzyme Inhibitors; D007093:Imidazoles; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D016718:Arachidonic Acid; D013930:Thromboxane-A Synthase