Roger P. Dickinson

UK-37,248, A novel, selective thromboxane synthetase inhibitor with platelet anti-aggregatory and anti-thrombotic activity

Abstract UK-37,248, 4-[-2-(1H-imidazol-1-yl)ethoxy] benzoic acid hydrochloride, in a human platelet microsomal preparation of thromboxane (Tx) synthetase, potently inhibited TxB2 production, IC50 = 3×10−9M. In contrast, prostaglandin (PG) endoperoxide synthesis from ram seminal vesicle microsomes was unaffected by concentrations of UK-37,248 up to 1×10−4M. Similarly UK-37,248 had minimal effects upon prostacyclin (PGI2) synthesis by pig aortic microsomes. Evidence for a re-direction of arachidonate (AA) metabolism from Tx-synthesis towards PGI2 synthesis was obtained using a rabbit isolated perfused lung preparation. Concentrations of UK-37,248 from 10−7 − 10−6M infused into the pulmonary artery selectively reduced TxA2 production from AA but increased the release of PGI2 and other PGs. In anaesthetised rabbits, fifteen minutes after injection of 0.3mg/kg i.v. UK-37,248, TxB2 production was reduced by 75%. In dogs the compound was similarly effective, lmg/kg p.o. inhibiting TxB2 production by 79% two hours after dosing. Aggregation of human platelet-rich plasma in vitro , initiated by threshold collagen, was inhibited by UK-37,248 (IC50 = 4.8×10−6M). UK-37,248, 2mg/kg p.o. prevented AA-induced mortality in rabbits and reduced the associated thrombosis, vasospasm and elevation of plasma TxB2.

Novel antifungal 2-aryl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol derivatives with high activity against aspergillus fumigatus.

Abstract Replacement of one triazole ring of fluconazole with 4-pyridinyl leads to an increase in activity against Aspergillus fumigatus. Introduction of an α-methyl group has a marked additional beneficial effect. Investigation of pyridinyl and pyrimidinyl analogues resulted in the identification of 30 (UK-109, 496, voriconazole) which has excellent potency against a broad range of fungal pathogens including A. fumigatus and Candida krusei.

Selective urokinase-type plasminogen activator (uPA) inhibitors. Part 1: 2-Pyridinylguanidines.

The identification of 2-pyridinylguanidines (e.g., 27 and 28) as selective inhibitors of urokinase-type plasminogen activator (uPA) is described. The X-ray crystal structure of 27 has been determined, and modelling has been used to predict binding in the enzyme active site.

The design and synthesis of a novel series of indole derived selective ETA antagonists

Abstract Conformational constraint has been used as the key design element in the identification of a series of potent and selective ET A antagonists. The most potent antagonist, 32 , (ET A IC 50 =0.55xa0nM) is 722-fold selective over the ET B receptor, as measured by binding experiments.

Discovery of potent and selective succinyl hydroxamate inhibitors of matrix metalloprotease-3 (stromelysin-1)

Structure activity relationships are described for a series of succinyl hydroxamic acids 4a-o as potent and selective inhibitors of matrix metalloprotease-3 (stromelysin-1). Optimisation of P1 and P3 groups gave compound 4j (MMP-3 IC50=5.9nM) which was >140-fold less potent against MMP-1 (IC50=51,000nM), MMP-2 (IC50=1790nM), MMP-9 (IC50=840nM) and MMP-14 (IC50=1900nM).

Selectivity of inhibition of matrix metalloproteases MMP-3 and MMP-2 by succinyl hydroxamates and their carboxylic acid analogues is dependent on P3′ group chirality

Structure-activity relationships are described for a series of succinyl hydroxamic acids 1a-o and their carboxylic acid analogues 2a-o as inhibitors of matrix metalloproteases MMP-3 and MMP-2. For this series (P1 = (CH2)3Ph, P2 = t-Bu) selectivity for the inhibition of MMP-2 was found to be strongly dependent on P3.

Selective urokinase-type plasminogen activator (uPA) inhibitors. Part 2: (3-Substituted-5-halo-2-pyridinyl)guanidines

Based on previous modeling predictions, a series of (3-substituted-5-chloro-2-pyridinyl)guanidines have been designed with good potency and selectivity for urokinase-type plasminogen activator (uPA). Compound 36 has a K(i) of 0.17 microM and greater than 300-fold selectivity with respect to tPA and plasmin.

Thromboxane modulating agents. 1. Design of 1-[(arylsulfonyl)amino] alkylindole derivatives as dual thromboxane synthase inhibitor/thromboxane receptor antagonists.

Abstract The design of a series of dual thromboxane synthase inhibitor/thromboxane receptor antagonists based on an indole thromboxane synthase inhibitor template is described. The indole-5-propanoic acid derivatives 17, 22 and 23 were found to be potent dual agents in vitro.

Thromboxane modulating agents. 2. Thromboxane receptor antagonists derived from the thromboxane synthase inhibitor dazmegrel.

Abstract The design of dual thromboxane synthase inhibitor/thromboxane receptor antagonists (e.g. 15 ) based on the structure of the thromboxane synthase inhibitor dazmegrel is described. More potent receptor antagonists (e.g. 16c ) result from replacement of the pyridinyl subsituent with 4-fluorophenyl. Modelling suggests the existence of more than one site capable of interacting with the aryl sulfonamide of TxA 2 receptor antagonists.

Chapter 10 Thromboxane Synthetase Inhibitors and Antagonists

Publisher Summary Thromboxane A2 (TxA2) plays a role in the maintenance of vascular homeostasis and may contribute to the pathogenesis of a variety of vascular disorders. It is produced by the metabolism of arachidonic acid (AA) in blood platelets and other tissues. Approaches toward limiting the effect of TxA2 have focused on either inhibiting its synthesis or blocking its action at its receptor sites by means of an antagonist. TxA2 is formed from the prostaglandin endoperoxide (PGH2) and inhibition of the synthetase enzyme may lead to an accumulation of endoperoxide. This is potentially beneficial because the accumulated PGH2 is available to be converted into PGI, although PGH does have similar properties to TxA2. On the other hand, TxA2 antagonlsts also block the actions of PGH2 but do not have the potential to elevate the PGI levels. Clinical studies with both TxA2 synthetase inhibitors and antagonists have, overall, failed to show convincing efficacy instable angina and unstable angina may be a more appropriate target. An important role for TxA2 in the pathophysiology of acute myocardial ischemia is indicated from studies in both animals and man, and further clinical work in this area is merited. However, despite extensive study, there is still uncertainty regarding the role of TxA2 in other disease states. Further clinical studies, coupled with improved techniques for monitoring TxA synthesis in vivo, is likely to help to define more clearly the role and relative merits of TxA2 synthetase inhibitor and antagonist therapy.