N-(cyclohexylcarbonyl)-D-phenylalanines and related compounds. A new class of oral hypoglycemic agents. 2

J Med Chem. 1989 Jul;32(7):1436-41. doi: 10.1021/jm00127a006.

Abstract

A series of analogues of N-(cyclohexylcarbonyl)-D-phenylalanine (5) have been synthesized and evaluated for their hypoglycemic activity. Relationships were studied between the activity and the three-dimensional structure of the acyl moiety, which was characterized by high-resolution 1H NMR spectroscopy and MNDO calculations. The role of the carboxyl group of the phenylalanine moiety was also studied by comparing the activities of the enantiomers, the decarboxyl derivative, the esters, and the amides of the phenylalanine derivatives. Thus, the structural requirements for possessing hypoglycemic activity was elucidated and a highly active compound, N-[(trans-4-isopropylcyclohexyl)carbonyl]-D-phenylalanine (13) was obtained, which showed a 20% blood glucose decrease at an oral dose of 1.6 mg/kg in fasted normal mice.

MeSH terms

  • Administration, Oral
  • Animals
  • Blood Glucose / analysis
  • Chemical Phenomena
  • Chemistry
  • Cyclohexanes / administration & dosage
  • Cyclohexanes / pharmacology*
  • Dogs
  • Hypoglycemic Agents*
  • Magnetic Resonance Spectroscopy
  • Male
  • Mice
  • Molecular Conformation
  • Nateglinide
  • Phenylalanine / administration & dosage
  • Phenylalanine / analogs & derivatives*
  • Phenylalanine / pharmacology

Substances

  • Blood Glucose
  • Cyclohexanes
  • Hypoglycemic Agents
  • Nateglinide
  • Phenylalanine