Angiotensin converting enzyme inhibitors: spirapril and related compounds.

The synthesis of spirapril (5), spiraprilat (25), their RSS stereoisomers, and their glycyl (18b) and lysyl (36, 37) analogues is described. These compounds were evaluated in vivo for inhibition of angiotensin converting enzyme (ACE), and selected compounds were evaluated for in vitro ACE inhibition (spirapril ID50 16 micrograms/kg; spiraprilat IC50 0.8 nM, ID50 8 micrograms/kg). In anesthetized rats, iv, esters 5 and 36 are more potent than enalapril, and diacids 25 and 37 are more potent than enalaprilat in vitro. In the conscious rats, orally, 5 and enalapril (2) showed potent and sustained activity at doses of 0.03-1 and 0.1-1 mg/kg, respectively. From this work, spirapril was selected for clinical evaluation as an antihypertensive agent.

Synthesis and pharmacological activity of angiotensin converting enzyme inhibitors: N-(mercaptoacyl)-4-substituted-(S)-prolines.

The synthesis of a series of N-(mercaptoacyl)-4-substituted-(S)-prolines (2 and 3) is described. These compounds were evaluated in vitro for inhibition of angiotensin-converting enzyme (ACE), and selected compounds were evaluated in vivo for ACE inhibition. The most potent compounds in vitro are 108, 109, 111, 114, and 116, having relative potencies of 1.0, 1.0, 1.3, 1.1, and 2.6 as compared to the potency of captopril. The most potent compounds in vivo intravenously are 108, 111, 114, 116, 117, and 97.

Relative activities of SCH 23390 and its analogs in three tests for D1/DA1 dopamine receptor antagonism.

Inhibitory activities of a series of analogs of SCH 23390 ((R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3- benzazepine) in which the 7-chloro group was substituted by bromo, fluoro, methyl and methoxy groups, respectively, were compared in three tests for D1 and DA1 dopamine (DA) receptor antagonism: inhibition of DA-induced renal vasodilation in the anesthetized dog (DA1 receptor model), inhibition of DA-stimulated adenylate cyclase in the striatum of adult female rats (D1 receptor model) and displacement of [3H]SCH 23390 in the striatal homogenates of male rats. In addition the D2 receptor affinity of each of the compounds chosen was assessed via displacement of [3H]spiperone binding from rat striatum. S-enantiomers of the Cl and CH3 analogs were 200- to 700-fold weaker than the respective R-enantiomers in all three tests. The activity of all the R-enantiomers was in the nanomolar range and varied no more than 8-fold in all three tests. The F analog in the ligand binding test was the only exception, which was 30-fold weaker than the C1 analog. All of the R-enantiomers studied showed much weaker affinity for the D2 receptor, as assessed by displacement of [3H]spiperone binding. Similar enantiomer selectivity and parallel affinities of the R-enantiomers in the prototype models for D1 and DA1 receptors strengthen the evidence in support of identity between the D1 and DA1 dopamine receptors. These results further indicate that displacement of SCH 23390 in the ligand binding test reflects affinity of a compound for D1 and DA1 dopamine receptors.

Synthesis and comparison of some cardiovascular properties of the stereoisomers of labetalol.

A useful method for the separation of labetalol into its two racemic diastereomers, as well as a stereoselective synthesis of its four stereoisomers, is described. The absolute stereochemistry of each isomer was determined by analysis of the DC spectra and confirmed by X-ray analysis. The alpha- and beta 1-adrenergic blocking properties, as well as the relative antihypertensive activities, have been measured in rats. The R,R isomer, 2a (SCH 19927), possesses virtually all of the beta 1-blocking activity elicited by labetalol and displays little alpha-blocking activity. In contrast, the S,R isomer, 3a, has most of the alpha-blocking activity. Of the four isomers, only 2a has antihypertensive potency comparable to that of labetalol. These findings, coupled with published data showing that labetalol possesses beta-adrenergic mediated peripheral vasodilating activity deriving essentially from its R,R isomer, lead to the following conclusion: The antihypertensive activity of labetalol can be ascribed to at least three identified complementary mechanisms, beta-adrenergic blockade, beta-adrenergic mediated vasodilatation, and alpha-adrenergic blockade, whereas the antihypertensive activity of 2a derives from the first two mechanisms only.

Alpha and beta adrenoceptor blocking properties of labetalol and its R,R-isomer, SCH 19927.

Labetalol is a mixture of four isomers. Its alpha and beta adrenergic blocking properties were compared to those of the R,R-isomer, SCH 19927. In anesthetized dogs, i.v. administration of both compounds produced competitive beta and alpha blockade as judged by inhibition of the tachycardia and vasopressor responses to i.v. injections of isoproterenol and phenylpherine, respectively. SCH 19927 was 3 to 4 times as potent as beta blocker, but only one-third as potent an alpha blocker as labetalol. Therefore, the separation of beta and alpha blocking activity of SCH 19927 clearly exceeded that of labetalol. SCH 19927 also demonstrated greater beta blocking potency than labetalol after oral administration to conscious dogs or rats that were subsequently pithed. SCH 19927 did not affect, whereas labetalol slightly reduced, pressor responses to sympathetic stimulation in the pithed rat. Both drugs were relatively devoid of intrinsic beta-1 sympathomimetic activity in the ganglion-blocked dog. It is concluded that SCH 19927 is a more potent beta adrenoceptor blocker and less potent alpha blocker than labetalol. The separation of adrenergic blocker activities indicates that steric requirements for alpha and beta blockade differ in the labetalol molecule.

Gastric antisecretory agents. 2. Antisecretory activity of 9-[(aminoalkyl)thio]-9H-xanthenes and 5-[(aminoalkyl)thio]-5H-[1]benzopyrano[2,3-b]pyridines.

A series of 9-[(aminoalkyl)thio]-9H-xanthenes (3-6) and 5-[(aminoalkyl)thio]-5H-[1]benzopyrano[2,3-b]pyridines (7-10) possessing gastric antisecretory activity in the rat and dog is described Many of the compounds possessed good activity in the pylorus-ligated rat and several inhibited histamine-stimulated gastric acid secretion in the dog. The mechanism of acid secretion inhibition is not related to anticholinergic or histamine (H2) receptor antagonism.

Synthesis of some 5-phenylhexahydroazepino[4,5-b]indoles as potential neuroleptic agents.

5-Phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (3a) and five derivatives have been prepared and screened for neuroleptic activity. None of the compounds antagonized methamphetamine aggregate toxicity in mice. A number of compounds, including 3a and its 3-methyl derivative 3d, showed activity in the antidepressant screens.