Peter E. Cross

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.

Long-acting dihydropyridine calcium antagonists. 9. structure activity relationships around amlodipine

Abstract The preparation of a range of 1,4-dihydropyridine analogues of amlodipine has been undertaken and their calcium antagonist activities on rat aorta have been evaluated. Increasing the size of the C5 ester group dramatically reduces calcium antagonist activity, a trend which would be compatible with the carbonyl group of that ester binding to the DHP receptor. Amlodipine analogues with extended C3 ester substituents also have lower potency than amlodipine, possibly because of disruption of a favourable interaction between the protonated amino group on the 2-substituent and the DHP receptor. Replacement of the 6-methyl substituent in amlodipine by alkoxyalkyl groups or electron-withdrawing groups is also detrimental to calcium antagonist activity.

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.

Rational resolution of the isosteric enantiomers of 6,11-dihydrodibenzo[b,e]thiepin-11-ol and conversion to the two isosteric diastereoisomers of the calcium channel blocker UK-74,756

Abstract Sulfoxidation of the (+)-Noe-lactol derivative of racemic 6,11-dihydrodibenzo[b,e]thiepin-11-ol broke the isosterism and converted an inseparable mixture of two compounds into a separable mixture of four. X-Ray structural determination on one of these and subsequent manipulation provided resolved 6,11-dihydrodibenzo[b,e]thiepin-11-ol and all four sulfoxides in known configurations, and enabled the resolution by synthesis of the two isosteric diastereoisomers of the calcium channel blocker UK-74,756.

Long-acting dihydropyridine calcium antagonists. 7. Compounds containing unsaturation in the 2-substituent on the 1,4-dihydropyridine ring

Abstract To evaluate the effect of introducing unsaturation into the 2-substituent of 1,4-dihydropyridines related to amlodipine ( 1 ), a number of alkene and alkyne analogues were prepared and their calcium antagonist activity was assessed. For several series of compounds, in vitro potency increased in the order alkane

Chapter 9. Antiarrhythmic Agents

Publisher Summary The cardiac arrhythmia suppression trial (CAST) study is designed to test the hypothesis that the suppressing asymptomatic premature ventricular beats with Class I anti-arrhythmic drugs would prolong the survival. The three drugs studied (encainide, flecainide, and moricizine) are chosen because they already had been shown to suppress the premature ventricular beats in post MI patients. Other anti-arrhythmic drugs, such as quinidine, procainamide, disopyramide mexilitene, and tocainide are not used, because previous studies suggests that they do not suppress arrhythmias as effectively or that the adverse effects precluded their long-term use in most patients. This chapter discusses the CAST study and its implications, and then gives an update on the Class I and Class III agents. The Class I antiarrhythmic agents, pirmenol, cibenzolin, and ethmozine (moricizine); the IC agents, encainide, flecainide, and propafenone; and the IB agents, mexiletine, and tocainide, have been discussed in this chapter. All Class I drugs are Na + channel inhibitors and they decrease the fast inward Na + current; they reduce the conduction velocity (V max ) in those cardiac structures, in which resting potential is negative to −60 mV. The sub-classes differ with respect to their mode of action on Na + channels and in their effects on action potential duration (APD). Class III agents exert their primary anti-arrhythmic activity by prolonging the cardiac action potential duration, and thereby the effective refractory period (ERP) with no effect on conduction. These electrophysiological changes are brought about by the blockade of cardiac potassium channels; this mechanism is not associated with the depression of the contractile function of the heart and may result in a slight enhancement of the contractile force.