Selective ET_AAntagonists. 5. Discovery and Structure−Activity Relationships of Phenoxyphenylacetic Acid Derivatives

Abstract

The fifth paper in this series describes the culmination of our investigations into the development of a potent and selective ET(A) receptor antagonist for the treatment of diseases mediated by ET-1. Receptor site mapping of several ET(A) antagonists prepared previously identified a common cationic binding site which prompted synthesis of phenoxyphenylacetic acid derivative 13a, which showed good in vitro activity (IC(50) 59 nM, rat aortic ET(A)). Optimization of 13a led to the identification of 27b, which exhibited an IC(50) of 4 nM. Although this did not translate into the expected in vivo potency, a compound of comparable in vitro activity, 27a (RPR118031A), showed a far better pharmacokinetic profile and in vivo potency (75 micromol/kg) and was duly proposed and accepted as a development candidate.

Practical Catalytic Asymmetric Synthesis of Diaryl-, Aryl Heteroaryl-, and Diheteroarylmethanols

“…15 Furthermore, enantioenriched diarylmethanols can be converted into diarylmethane derivatives via S N 2 substitution at the C-O bond without loss of ee 1. The diarylmethane motif is found in antimuscarinics,16 antidepressants,17 and endothelin antagonists 18…”

The Biophore Concept

“…Several recent examples provide an overview of the methods discussed above. The use of this model guided the development of a series combining properties from the different lead series and, subsequently, led to the discovery of a development candidate RPR118031A [117]. A group at Rhone-Poulenc derived a two-point pharmacophore from two published antagonists, a cyclic pentapeptide and a ligand based on the triterpene framework (Fig.…”

Endothelin Receptor Antagonists - An Overview

“…Starting with a modest in-house lead, 2,4-dibenzyloxybenzoic acid, group at Rhone-Poulenc Rorer carried out extensive SAR of phenoxyphenyl acetic acid; Fig. (22) and discovered RPR118031A [117], a developmental candidate with not only good ET A activity (IC 50 = 6-7 nM) but acceptable pharmacokinetic profile as well (t 1/2 = 7.4 h, oral bioavailability 89%). Interestingly, the analogue (RPR117820A) with better activity showed poor bioavailability (9%) and low half life (t 1/2 = 12 min).…”