John Christopher Danilewicz

Synthesis of 1,2,5,6-Tetrahydro-3-pyridinylalanine: A Key Intermediate in the Preparation of Thrombin Inhibitor UK-239,326

Abstract A short synthesis of N-protected 1,2,5,6-tetrahydro-3-pyridinylalanine derivatives (8–10) was accomplished using a simple procedure of quaternization of (3-pyridyl)alanine 6 with benzyl bromide followed by reduction with NaBH4. Amino acid 10 was then converted to thrombin inhibitor UK-239,326 (2), which required the sequential functionalization of four amines to give four different functional groups (viz., sulfonamide, carboxamide, guanidine, and methylamine).

Chapter 10. Agents for the Treatment of Heart Failure

Publisher Summary Drugs used for treating heart failure are primarily the cardiac glycosides and diuretics. The cardiac glycosides are positive inotropic agents— that is, they increase the force of myocardial contraction, although their effect on cardiac rhythm may also be important. Recently, attention is turning to the response of the peripheral vasculature to the failing heart and vasodilators are being increasingly investigated. This chapter reviews such recent developments. Cardiac glycosides are particularly effective in cases where cardiac rhythm is accelerated. Indeed, their use in failure accompanied by normal sinus rhythm is questionable. A complicating factor in the interpretation of the mode of action of the cardiac glycosides in vivo is that they have neuroexcitatory activity. A significant vagomimetic action is demonstrated at therapeutic doses, and this probably accounts for their effectiveness in atrial flutter and fibrillation. In the use of vasodilators, the mode of action is interpreted by considering preload that determines ventricular filling pressure; the inotropic state of the heart, which is the ability to perform work; and after load, which is a measure of arterial impedance to the ejection of blood during systole. In health, stroke volume can be maintained within limits in the face of varying outflow impedance and, therefore, vasodilatation may produce hypotension if cardiac output is not sufficiently augmented by the reflex increase in heart rate. In decompensated heart failure, however, where no cardiac reserve exists, stroke volume bears a much accentuated inverse relationship to output impedance, so that a reduction in peripheral resistance causes an increase in stroke volume.

Chapter 9. Antihypertensive Agents

Publisher Summary Calcium antagonists are being increasingly studied in hypertension and nifedipine effectively lowers blood pressure in man producing only a small increase in heart rate on chronic therapy. Unlike other vasodilators, there is little change in PRA or fluid retention, suggesting an additional renal action. Modification of both the ester function and nitro-group in this dihydropyridine series has a marked effect on vasodilator activity. Treatment of patients with a diastolic blood pressure (DBP) >= 100 mm Hg reduces the incidence of stroke, while the hypertension detection and follow-up program indicates that effective management of milder hypertension (DBP 90–104 mm Hg.) reduces mortality. A review of captopril in the treatment of hypertension has been published. Attainment of blood pressure control varies widely (35%-90%), and development of tolerance has been described in a small group of patients. The combination of captopril and thiazide seems particularly useful as captopril represses the rise in AII and aldosterone levels, as well as the hypokalemia induced by the diuretic. Although clonidine is reported to reduce renovascular resistance chronically, a reduction in renal blood flow, associated with an increase in plasma renin concentration, has been noted in some patients. In a multicentre comparison, guanabenz, in contrast to a-methyldopa, did not cause fluid retention.

Chapter 8. Antihypertensive Agents

Publisher Summary The relative contributions of environmental and genetic factors to hypertensive disease may emerge from the studies of different racial groups. The prevalence of hypertension is greater in black than in white Americans and is more commonly of the low renin type. This has led to the proposal that the former population has evolved an enhanced capacity to retain salt and water that, though appropriate to a sub-tropical habitat, proves disadvantageous on exposure to a high dietary salt intake. Studies with erythrocytes from hypertensive patients and their offspring have led to the proposal that EH may be because of a reduced capacity to extrude intracellular Na through an inherited disorder of the furosemide-sensitive Na+, K+-co-transport system. Prevention of the development of hypertension in SHR by propranolol could be because of central inhibition of sympathetic vasomotor tone and furthermore, the drug does accumulate in specific areas of rat brain involved with cardiovascular control. The antihypertensive activity of trimazosin is accompanied by an increase in renal blood flow, and this may be particularly useful when kidney function is impaired. Initial reports with tiodazosin indicate that the drug lowers blood pressure in man and has a plasma half-life of 8 hour.