Synthesis and Use of 3-amino-4-phenyl-2-piperidones and 4-amino-2-benzazepin-3-ones as Conformationally Restricted Phenylalanine Isosteres in Renin Inhibitors

J Med Chem. 1992 Mar 6;35(5):833-46. doi: 10.1021/jm00083a006.

Abstract

The design of P2-P3 conformational restrictions in renin inhibitors by the use of a renin computer graphic model led to the synthesis of inhibitors containing N-Boc, N-acetyl, and N-phthalyl derivatives of 3(S)-amino-4(R,S)-2-piperidones and 4(S)-amino-2-benzazepinones in place of phenylalanine in the control compound N-acetyl-L-phenylalanyl-N-[4(S)-[(butylamino)carbonyl]-1(S)- (cyclohexylmethyl)-2(S)-hydroxy-5-methylhexyl]-L-norleuci namide (32). The piperidone inhibitors were prepared by utilization of the Evans chiral auxilliary to introduce the amino group with enantioselectivity and also to act as a leaving group in an intramolecular cyclization to the piperidone. The most potent inhibitor, 3(S)-(acetylamino)-alpha(S)-butyl-N-[4(S)- [(butylamino)carbonyl]-1(S)-(cyclohexylmethyl)-2(S)-hydroxy-5- methylhexyl]-2-oxo-4(R)-phenyl-1-piperidineacetamide (18, IC50 = 21 nM), was 25-fold less potent than the acyclic control 32. Considerable dependence of potency with the size of the P4 derivative was observed as had been expected based on the presynthetic modeling studies. Attempts to rationalize the observed potencies on the basis of further molecular modeling studies suggested that the loss in inhibitor potency was due to the conformational restrictions distorting the 3S center from the geometry present in the putative extended conformation present when the inhibitor is bound within the renin active site.

Publication types

  • Comparative Study

MeSH terms

  • Benzazepines / chemical synthesis*
  • Benzazepines / pharmacology
  • Computer Simulation
  • Cyclization
  • Dipeptides / chemistry*
  • Dipeptides / pharmacology
  • Humans
  • Models, Molecular
  • Molecular Conformation
  • Molecular Structure
  • Phenylalanine / analogs & derivatives*
  • Piperidones / chemical synthesis*
  • Piperidones / pharmacology
  • Renin / antagonists & inhibitors*
  • Renin / blood
  • Structure-Activity Relationship
  • X-Ray Diffraction

Substances

  • Benzazepines
  • Dipeptides
  • Piperidones
  • N-acetylphenylalanyl-N-(4-((butylamino)carbonyl)-1-(cyclohexylmethyl)-2-hydroxy-5-methylhexyl)norleucinamide
  • Phenylalanine
  • Renin