Captopril (SQ 14,225) (d-3-mercapto-2-methylpropanoyl-l-proline): A novel orally active inhibitor of angiotensin-converting enzyme and antihypertensive agent

Relatively potent and specific in vitro and in vivo (oral or intravenous) inhibition of angiotensin-converting enzyme by a nonpeptidic compound, captopril (SQ 14,225; d-3-mercapto-2-methylpropanoyl-l-poline), was demonstrated in excised guinea pig ileum and in rats, rabbits, cats, dogs, and monkeys. The design of captopril was based on a hypothetical model of the active site of the enzyme. Captopril, in vitro or in vivo, was about ten times as potent as teprotide. Inhibition of angiotensin-converting enzyme was evaluated in vitro and in vivo by inhibition of the contractile or vasopressor activity of angiotensin I or by augmentation of the contractile or vasodepressor activity of bradykinin. Acute of subacute dosage with captopril moderately to markedly lowered the blood pressure of the renin-dependent aorticligated and the conscious two-kidney Goldblatt hypertensive rat; in the latter, the effect was intensified by concomitant dosage with a thiazide diuretic. Furthermore, the life-prolonging effects of captopril in renal hypertensive rats were augmented by a thiazide diuretic. In the two-kidney Goldblatt rat, acute captopril (p.o.) was about ten times as potent as teprotide (s.c.) in lowering blood pressure. Acute or subacute oral doses of captopril moderately reduced the blood pressure of the spontaneously hypertensive Wistar-Kyoto rat; chronic dosage almost normalized blood pressure. Captopril produced little or no hypotension in the saltreplete normotensive Wistar-Kyoto rat. Bilateral nephrectomy virtually abolished the hypotensive activity of captopril in the spontaneous hypertensive rat. The results suggest that captopril acts in large part by inhibiting the renin-angiotensin-aldosterone system to reduce elevated blood pressure, especially in renindependent models of hypertension; the roles of the kallikrein-kinin-prostaglandin systems and sodium balance remain to be elucidated. Captopril also lowers blood pressure in apparently non-renin-dependent types of hypertension by mechanisms that are as yet undefined.     

Design of new antihypertensive drugs: Potent and specific inhibitors of angiotensin-converting enzyme

The similarity of the biologically important enzyme angiotensin-converting enzyme to the structurally characterized digestive enzyme carboxypeptidase A has led us to develop a hypothetical model of the mechanism of binding of substrates to its active site. In this model, a positively charged group on the enzyme forms an ionic bond with the negatively charged carboxyl group of the substrate; a hydrogen bonding group of the enzyme binds with the terminal peptide bond of the substrate, and the tightly bound zinc ion of the enzyme binds to the penultimate (scissile) peptide bond of the substrate. Succinyl-l-proline (SQ 13,745) was synthesized as a potential inhibitor of angiotensin-converting enzyme by analogy to d-2-benzylsuccinic acid, an inhibitor of carboxypeptidase A; it was a moderately potent but specific inhibitor of the enzyme. Structure-activity studies carried out using the hypothetical model as a guide led to the synthesis of d-2-methyl-succinyl-l-proline (SQ 13,-297) and d-2-methylglutaryl-l-proline (SQ 14,-102), more potent inhibitors of the enzyme that were shown to be orally active in rats. Attempts to replace the zinc-binding carboxyl group of these compounds with groups with greater affinity for zinc have led to the synthesis of extremely potent inhibitors such as 3-mercapto-propanoyl-l-proline (SQ 13,863) and d-3-mercapto-2-methylpropanoyl-l-proline (SQ 14,225). The most active compound, SQ 14,225, is a purely competitive inhibitor of angiotensin-converting enzyme with an enzyme-inhibitor dissociation constant (K_i) of 1.7 × 10⁻⁹M. It is an extremely potent and specific inhibitor of angiotensin-converting enzyme and appears to have great potential for the treatment of hypertensive disease.     

Role of the thyroid in the development of the obese-hyperglycemic syndrome in mice (obob)

Some aspects of thyroid activity in obese mice were investigated. Protein-bound iodine (PBI), hormonal iodine (HI), total thyroxin (TT₄) in plasma, ¹³¹I uptake and release from the thyroid and apical cell width, and nuclear volume of the thyroid epithelial cells were determined in various age groups in obese and nonobese mice. On the basis of the results of the comparison between the obese and nonobese mice, it was concluded that the genetically obese mouse is hypothyroid. This conclusion is supported by the finding that body temperature that is low in obese mice, can be raised by thyroxin injections to normal values. An increased sensitivity for exogenous thyroxin can be shown also in the induction of liver mitochondrial α-glycerophosphate dehydrogenase. The possibility that hypothyroidism is one of the causes of the obese-hyperglycemic syndrome is discussed.