Inhibitors of cholesterol biosynthesis. 2. 1,3,5-trisubstituted [2-(tetrahydro-4-hydroxy-2-oxopyran-6-yl)ethyl]pyrazoles.

A series of 1,3,5-trisubstituted pyrazole mevalonolactones were prepared and evaluated for their ability to inhibit the enzyme HMG-CoA reductase in vitro. Since previous studies suggested that the 5-(4-fluorophenyl) and 3-(1-methylethyl) substituents afforded optimum potency, attention was focused on variations in position 1 of the pyrazole ring. Biological evaluation of analogues bearing a variety of 1-substituents suggested that, although most substituents were tolerated, none afforded an advantage over phenyl, which exhibited potency comparable to that of compactin in vitro.

Cardioselective beta-adrenergic blocking agents. 1. 1-((3,4-Dimethoxyphenethyl)amino)-3-aryloxy-2-propanols.

A series of 1-amino-3-aryloxy-2-propanols has been synthesized and examined for cardioselective beta-blockade. The introduction of the (3,4-dimethoxyphenethyl)amino group lead to the most cardioselective agents. Structure-activity relationships are discussed. Of the compounds tested 1-[(3,4-dimethoxyphenethyl)amino]-3-(m-tolyloxy)-2-propanol was selected for clinical trial because of optimal potency and selectivity.

Synthesis and antiarrhythmic activity of cis-2,6-dimethyl-alpha,alpha-diaryl-1-piperidinebutanols.

A series of alpha,alpha-diaryl-1-piperidinebutanols was evaluated for antiarrhythmic activity in the coronary ligated dog model. Structure-activity relationship studies indicated that the 2,6-dimethylpiperidine group yielded compounds with the best antiarrhythmic profiles in this series. The length of the methylene chain separating the diarylcarbinol and the amino group was not crucial. Substitution of a hydrogen or a number of functional groups for the hydroxyl group had little effect on efficacy or duration but yielded compounds that produced severe tachycardias. Replacement of one of the aryl groups by hydrogen or a pyridinyl or cyclohexyl group had little effect on efficacy but decreased the duration of action. Compound 18 (pirmenol) was ultimately chosen for further studies and is now being investigated in man.

Inhibitors of cholesterol biosynthesis. 1. trans-6-(2-pyrrol-1-ylethyl)-4-hydroxypyran-2-ones, a novel series of HMG-CoA reductase inhibitors. 1. Effects of structural modifications at the 2- and 5-positions of the pyrrole nucleus.

A novel series of trans-6-(2-pyrrol-1-ylethyl)-4-hydroxypyran-2-ones and their dihydroxy acid derivatives were prepared and evaluated for their ability to inhibit the enzyme HMG-CoA reductase in vitro. A systematic study of substitution at the 2- and 5-positions of the pyrrole ring revealed that optimum potency was realized with the 2-(4-fluorophenyl)-5-isopropyl derivative 8x, which possessed 30% of the in vitro activity of the potent fungal metabolite compactin (I). A molecular modeling analysis led to the description of a pharmacophore model characterized by (A) length limits of 5.9 and 3.3 A for the 2- and 5-substituents, respectively, as well as an overall width limit of 10.6 A across the pyrrole ring from the 2- to the 5-substituent and (B) an orientation of the ethyl(ene) bridge to the 4-hydroxypyran-2-one ring nearly perpendicular to the planes of the parent pyrrole, hexahydronaphthalene, and phenyl rings of the structures examined (Figure 3, theta = 80-110 degrees). Attempts to more closely mimic compactin's polar isobutyric ester side chain with the synthesis of 2-phenylpyrroles containing polar phenyl substituents resulted in analogues with equal or slightly reduced potencies when compared to the 2-[(unsubstituted or 4-fluoro)phenyl]pyrroles, supporting the hypothesis that inhibitory potency is relatively insensitive to side-chain polarity or charge distribution in this area.

Derivatives of the potent angiotensin converting enzyme inhibitor 5(S)-benzamido-4-oxo-6-phenylhexanoyl-L-proline: effect of changes at positions 2 and 5 of the hexanoic acid portion.

Several derivatives of the potent angiotensin converting enzyme inhibitor 5(S)-benzamido-4-oxo-6-phenylhexanoyl-L-proline (1) were synthesized and tested for converting enzyme inhibition activity and blood pressure lowering effects in rats. One compound, 5(S)-benzamido-2(R)-methyl-4-oxo-6-phenylhexanoyl-L-proline (2a), had and I50 against angiotensin converting enzyme of 1.0 x 10(-9) M and is the most potent inhibitor prepared thus far in this class of compounds. Testing of 2a orally at 30 mg/kg for inhibition of the angiotensin I induced blood pressure increase in conscious normotensive rats gave 100% inhibition that required 143 min before the angiotensin I blood pressure response returned to 70% of the pretreatment control response. In the conscious renal hypertensive rat, 2a given orally at a dose of 3 mg/kg caused a lowering of blood pressure that reached its maximum of 40 mmHg 8 h following drug administration.

Synthesis of novel angiotensin converting enzyme inhibitor quinapril and related compounds. A divergence of structure-activity relationships for non-sulfhydryl and sulfhydryl types.

The synthesis and angiotensin converting enzyme (ACE) inhibiting activities of quinapril (CI-906, 22), its active diacid (CI-928, 33), and its dimethoxy analogue (CI-925, 25) are reported. These tetrahydro-3-isoquinolinecarboxylic acid derivatives possess equivalent in vitro potency and in vivo efficacy to enalapril. Sulfhydryl analogues with the same structural variation are also highly potent. In contrast, tetrahydro-1-isoquinolinecarboxylic acid and homologous isoindoline-1-carboxylic acid analogues show a striking divergence in potency between the two types, sulfhydryl analogues being essentially inactive, while non-sulfhydryl analogues are equipotent with the proline prototype. This is the first evidence suggesting that alternate binding modes may exist for the two major structural classes of small molecule ACE inhibitors.

Inhibitors of cholesterol biosynthesis. 3. Tetrahydro-4-hydroxy-6-[2-(1H-pyrrol-1-yl)ethyl]-2H-pyran-2-one inhibitors of HMG-CoA reductase. 2. Effects of introducing substituents at positions three and four of the pyrrole nucleus.

A series of trans-tetrahydro-4-hydroxy-6-[2-(2,3,4,5-substituted-1H-pyrrol-1-yl) ethyl]-2H-pyran-2-ones and their dihydroxy acids were prepared and tested for their ability to inhibit the enzyme HMG-CoA reductase in vitro. Inhibitory potency was found to increase substantially when substituents were introduced into positions three and four of the pyrrole ring. A systematic exploration of structure-activity relationships at these two positions led to the identification of a compound ((+)-33,(+)-(4R)-trans-2-(4-fluororphenyl)-5-(1-methylethyl)-N,3- diphenyl-1- [(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-4- carboxamide) with five times the inhibitory potency of the fungal metabolite compactin.

Synthesis and antiarrhythmic activity of alpha-[(diarylmethoxy)methyl]-1-piperidineethanols.

A series of alpha-[(diarylmethoxy)methyl]-1-piperidineethanols was evaluated for antiarrhythmic activity in the coronary artery ligated dog model. Structure-activity relationship studies indicated that the 2,6-dimethylpiperidine group afforded the best antiarrhythmic agents in this series and was essential for long duration of action. This investigation indicated that quaternary ammonium salts were not essential for a long duration of action. It was also shown that the antiarrhythmic activity could be separated from the tachycardia frequently caused by this type of agent.

Inhibitors of acyl-CoA:cholesterol acyltransferase. 1. Identification and structure-activity relationships of a novel series of fatty acid anilide hypocholesterolemic agents.

A series of fatty acid anilides was prepared, and compounds were tested for their ability to inhibit the enzyme acyl-CoA:cholesterol acyltransferase (ACAT) in vitro and to lower plasma total cholesterol and elevate high-density lipoprotein cholesterol in cholesterol-fed rats in vivo. The compounds reported were found to fall into two subclasses with different anilide SAR. For nonbranched acyl analogues, inhibitory potency was found to be optimal with bulky 2,6-dialkyl substitution. For alpha-substituted acyl analogues, there was little dependence of in vitro potency on anilide substitution and 2,4,6-trimethoxy was uniquely preferred. Most of the potent inhibitors (IC50 less than 50 nM) were found to produce significant reductions in plasma total cholesterol in cholesterol-fed rats. Additionally, in vivo activity could be improved significantly by the introduction of alpha,alpha-disubstitution into the fatty acid portion of the molecule. A narrow group of alpha,alpha-disubstituted trimethoxyanilides, exemplified by 2,2-dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide (39), was found to not only lower plasma total cholesterol (-60%) in cholesterol-fed rats but also elevate levels of high-density lipoprotein cholesterol (+94%) in this model at the screening dose of 0.05% in the diet (ca. 50 mg/kg).

Synthesis and angiotensin-converting enzyme inhibitory activity of 3-(Mercaptomethyl)-2-oxo-1-pyrrolidineacetic acids and 3-(Mercaptomethyl)-2-oxo-1-piperidineacetic acids.

A number of gamma- and delta-lactam derivatives were synthesized and their in vitro angiotensin-converting enzyme (ACE) inhibitory activities were compared. The structures of these compounds were designed to include many of the important features of captopril. The synthesis involved the preparation of a variety of novel 3-methylene-2-pyrrolidinones (3-5 and 16) and 3-methylene-2-piperidinones (3a-5a, 10-12, and 17). The key intermediate 3-methylenelactams 3 and 3a were obtained from 3-(hydroxymethyl)lactams 2 and 2a by a direct dehydration with dicyclohexylcarbodiimide using cuprous iodide as a catalyst. Introduction of the sulfhydryl group was accomplished by a Michael addition of these alpha, beta-unsaturated lactams. The compound with the highest in vitro activity was 3-(mercaptomethyl)-2-oxo-1-piperidineacetic acid (7a). The activity of the 7a both in vitro and in vivo (dog) was shown to be less than that of captopril by a factor of about 100.

Novel synthesis of (S)-1-[5-(benzoylamino)-1,4-dioxo-6-phenylhexyl]-L-proline and analogues: potent angiotensin converting enzyme inhibitors.

A new approach was developed for the synthesis of (S)-1-[5-(benzoylamino)-1,4-dioxo-6-phenylhexyl]-L-proline (1) and 23 analogues. The delta-(acylamino)-gamma-keto acid intermediates were obtained by a modified Dakin--West reaction using 3-carbomethoxypropionyl chloride. Acylation of L-proline and recrystallization of the mixture of diastereomers gave the optically pure title compound in three reaction steps. The in vitro angiotensin converting enzyme (ACE) inhibitory activity of 1 was confirmed. Some of the novel analogues (6, 11, 13, and 17) were also found to be potent inhibitors of ACE in vitro with an IC50 of 1.4-8.8 x 10(-9) M (IC50 for captopril = 0.9 x 10(-8) M). In vivo these compounds (6, 11, 17, and 18) were much less active than captopril, especially by the oral route. Against angiotensin I (AI) challenge in normotensive conscious rats, 1 and 6 produced less than 50% inhibition at 30 mg/kg po but 57 to 82% inhibition at 3 mg/kg iv. Inhibition by both routes lasted less than 1 h. In renal hypertensive rats, 1 and 15 of its analogues failed to produce significant blood pressure lowering effects, in contrast to the marked effects of captopril. Near maximum inhibition of AI was achieved by continuous intravenous infusions of 1 and 20, suggesting that limited oral activity may by due to degradation and/or clearance.

Synthesis and structure-activity relationships of potent new angiotensin converting enzyme inhibitors containing saturated bicyclic amino acids.

The synthesis of a series of novel, potent angiotensin converting enzyme (ACE) inhibitors containing saturated bicyclic amino acids in place of proline is described. Octahydroindole-2-carboxylic acid, octahydroisoindole-1-carboxylic acid, and octahydro-3-oxoisoindole-1-carboxylic acid can replace proline in both sulfhydryl and non-sulfhydryl ACE inhibitors to give compounds equipotent to captopril and enalapril both in vitro and in vivo. Structure-activity relationships are discussed. Compound 11a (CI-907, indolapril) has advanced to clinical evaluation.