Substrate analog renin inhibitors containing replacements of histidine in P2 or isosteres of the amide bond between P3 and P2 sites

Abstract

Incorporation of beta-alanine or gamma-aminobutyric acid in position P2 of ACHPA or Leu psi [CHOHCH2]Val-based tetrapeptides gave highly active renin inhibitors (compounds V, VI, and XVII) with high specificity for renin and a remarkable stability against chymotrypsin. Replacement of the amide bond between P2 and P3 by isosteres (ketomethylenes, hydroxyethylenes, and the corresponding thio-insertion analogues) led to compounds (VIII-XIII, XVIII, and XIX) with renin inhibitory activity in the nanomolar range. Oral activity was achieved by incorporation of polar functionalities at the N-terminus of beta-alanine-containing tetrapeptides. One of these compounds (XXVIII) was chosen for further studies. This inhibitor demonstrated excellent efficacy and a long duration of action after intravenous and oral administration to cynomolgus monkeys.

Versatile and Stereoselective Synthesis of Diamino Diol Dipeptide Isosteres, Core Units of Pseudopeptide HIV Protease Inhibitors

“…The first step consists of the synthesis of the trans -enones 6 . Our initial attempts to prepare 6a by the Wittig reaction of the β-keto phosphonium salt 5 failed at an early stage as we could not obtain 5 from the known bromide 4 . However, β-keto phosphonates 3 are readily prepared from amino esters 2 ; thus, trans -enones 6 were obtained in excellent yield by the Horner−Wadsworth−Emmons reaction of 3 with the appropriate aldehyde, in dry ethanol, in the presence of 1 equiv of potassium carbonate (Scheme ).…”

X‐ray structures of aza‐proline‐containing peptides

“…After the pioneering works of Hess et al (4) and Gante & Lautsch ( 5 ) in the aza-peptides field, other pseudopeptides including various aza-residues, denoted by AzXaa in the following, have been prepared and studied mainly from a biological point of view. They have been introduced in analogues of angiotensin I1 (4,6), oxytocin (7), eledoisin (8-lo), luliberin (1 1-16), somatostatin (17), enkephalin (18,19) and in various protease inhibitors (20)(21)(22)(23)(24)(25)(26). Many aza-surrogates of the proteinaceous amino acids have been described, including those bearing an aliphatic side-chain (27,28) as Abbreviations: Ac, acetyl; AzAla, aza-analogue of alanine; AzAsn, aza-analogue of asparagine; AzAsp, aza-analogue of aspanic acid; AzPro, aza-analogue of proline; AzXaa, aza-analogue of an amino acid residue; Boc, terr-butyloxycarbonyl; Me, methyl; iPr, isopropyl; Piv, pivalyl; Z, benzyloxycarbonyl.…”

Design, Synthesis, and Biological Evaluation of Novel Fluorinated Ethanolamines

“…The bis-fluorinated bromohydrin 34 was obtained by following an identical three-step sequence in 58 % yield (95:5 d.r.). The stereochemical elucidation of the reduction products was possible by comparing the 1 H NMR spectra and optical rotation data of 35 to that reported for the same compound by Raddatz et al [32] The epoxides 36 and 37 were obtained quantitatively upon treatment of the corresponding bromohydrin precursors with potassium hydroxide in ethanol. These intermediates were further elaborated to our target compounds 1 and 29 (Scheme 12) following our developed epoxide opening-amide formation strategy (vide supra).…”

“…This problem could be circumvented by performing the bromination on the silyl enol ether (generated upon treatment of 33 with LiHMDS and TMSCl). [31] The resulting bromoketone was directly submitted to reductive conditions (NaBH 4 in EtOH) [32] to yield alcohol 35 almost exclusively (95:5 d.r.) in acceptable yields (48 %, 3 steps).…”