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We have discovered a novel class of endothelin (ET) receptor antagonists through pharmacophore analysis of the existing non-peptide ET antagonists. On the basis of this analysis, we determined that a pyrrolidine ring might replace the indian ring in SB 209670. The resultant compounds were readily prepared and amenable to extensive SAR studies. Thus a series of N-substituted trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrroli din e-3- carboxylic acids (8) have been synthesized and evaluated for binding at ET(A) and ET(B) receptors. Compounds with N-acyl and simple N-alkyl substituents had weak activity. Compounds with N-alkyl substituents containing ethers, sulfoxides, or sulfones showed increased activity. Much improved activity resulted from compounds where the N-substituents were acetamides. Compound 17u (A-127722) with the N,N-dibutylacetamide substituent is the best of the series. It has an IC(50)=0.36 nM for inhibition of ET-1 radioligand binding at the ET(A) receptor, with a 1000-fold selectivity for the ET(A) vs the ET(B) receptor. It is also a potent inhibitor (IC(50)=0.16 nM) of phosphoinositol hydrolysis stimulated by ET-1, and it antagonized the ET-1-induced contraction of the rabbit aorta with a pA(2)=9.20. The compound has 70% oral bioavailability in rats.

The aim of this study was the discovery of nonpeptide renin inhibitors with much improved oral absorption, bioavailability, and efficacy, for use as antihypertensive agents. Our prior efforts led to the identification of A-74273 [1,R = 3-(4-morpholino)propyl], with a bioavailability of 26 +/- 10% [10 mg/kg intraduodenally (id), dog]. In vivo metabolism studies of A-74273 showed that the morpholino moiety underwent metabolic degradation. Computer modeling of A-74273 bound to renin indicated that the C-terminus was involved in a hydrogen-bonding network. New C-terminal groups were examined in two series of nonpeptides for effects on renin binding potency, lipophilicity (log P), and aqueous solubility. Those groups which possessed multiple hydrogen-bonding ability (3,5-diaminotriazole, cyanoguanidines, morpholino) provided particularly potent renin binding. Intraduodenal bioavailabilities of selected compounds, evaluated in rats, ferrets, and dogs, were higher for inhibitors with moderate solubility as well as moderate lipophilicity, in general. Although the absolute values varied substantially among species, the relative ordering of the inhibitors in terms of absorption and bioavailability was reasonably consistent. Such well absorbed inhibitors (e.g. 41, 44, and 51) were demonstrated as highly efficacious hypotensive agents in the salt-depleted dog. We report here the discovery of a series of efficacious nonpeptide renin inhibitors based on the 3-azaglutaramide P2-P4 replacement, the best of which showed id bioavailabilities > 50% in dog.

We describe the development of a series of soluble, potent, and bioavailable nonpeptide renin inhibitors. These inhibitors derived from a series of novel nonpeptide renin inhibitors which were recently identified in our laboratories, by alteration of the nature of the C-terminus (P2') of the molecules. Introduction of basic substituents into modified hydroxyethylene dipeptide isosteres gave inhibitors with improved solubility as well as improved potency against human plasma renin. In addition, these modifications produced inhibitors which displayed markedly improved intraduodenal bioavailability in both the ferret and cynomolgus monkey. We also present data which demonstrate excellent efficacy in the monkey for A-74273 (65), with an intraduodenal bioavailability of 16 +/- 4% in the monkey, compared to 1.7 +/- 0.5% for the dipeptide renin inhibitor enalkiren (A-64662, 75). A-74273 is an example of a nonpeptide inhibitor which possesses a good balance of the desirable properties of potency, solubility, and lipophilicity and which is well absorbed into the intestine.