Recent developments of thromboxane modulators

Abstract

Thromboxane A 2 (TXA 2 ) is a labile product formed from arachidonic acid by the way of cyclooxygenase and thromboxane synthase. An overproduction of TXA 2 has been detected in a series of diseases where this eicosanoid is assumed to contribute to the underlying pathomechanisms by its potent stimulation of platelet aggregation and smooth muscle contraction. Indeed, literature supports participation of TXA 2 in several physiopathological mechanisms such as tumour growth and metastasis, pre-eclampsia, asthma, pulmonary hypertension and in the progression of ischaemic injury after coronary artery occlusion. This evidence provides a strong rationale for pursuing TXA 2 blocking strategies in drug development. Therefore, TXA 2 receptor antagonists, thromboxane synthase inhibitors and drugs which combine both activities have been developed. Of the 28 thromboxane modulator patents reviewed from January 1997 to December 2000, 16 relate to thromboxane receptor antagonists (TXRAs), seven to thromboxane synthase inhibitors and five to agents combining both activities. Of these patents, 19 claim new chemical structures, five claim a new use, one claims combination therapy and three claim processes. This article focuses on latest discoveries and developments of novel TXA 2 modulators described in these patents.

Macrophages: An elusive yet emerging therapeutic target of atherosclerosis

“…[322][323][324] TXA2 actions are mediated through its TP receptor. 322,[325][326][327] The COX-1 inhibitors, like aspirin, have the advantage of inhibiting TXA2 production, but under such conditions production of other TP receptor ligands, such as hydroxyeicosatetraenoic acids 328 and F 2 -IPs 329 that are formed by endothelial cells, circulating monocytes and macrophages in the atherosclerotic plaque in response to oxidative stress, remains unaltered and hence the strategy may not be fully effective. Blockade of thromboxane effect by using TP receptor-specific antagonist S18886 has been found to be more beneficial.…”