1. Academic Validation
  2. Design and synthesis of new potent C2-symmetric HIV-1 protease inhibitors. Use of L-mannaric acid as a peptidomimetic scaffold

Design and synthesis of new potent C2-symmetric HIV-1 protease inhibitors. Use of L-mannaric acid as a peptidomimetic scaffold

  • J Med Chem. 1998 Sep 24;41(20):3782-92. doi: 10.1021/jm970777b.
M Alterman 1 M Björsne A Mühlman B Classon I Kvarnström H Danielson P O Markgren U Nillroth T Unge A Hallberg B Samuelsson
Affiliations

Affiliation

  • 1 Department of Chemistry, Linköping University, S-581 83 Linköping, Sweden.
Abstract

A study on the use of derivatized carbohydrates as C2-symmetric HIV-1 Protease Inhibitors has been undertaken. L-Mannaric acid (6) was bis-O-benzylated at C-2 and C-5 and subsequently coupled with Amino acids and amines to give C2-symmetric products based on C-terminal duplication. Potent HIV Protease Inhibitors, 28 Ki = 0.4 nM and 43 Ki = 0.2 nM, have been discovered, and two synthetic methodologies have been developed, one whereby these inhibitors can be prepared in just three chemical steps from commercially available Materials. A remarkable increase in potency going from IC50 = 5000 nM (23) to IC50 = 15 nM (28) was observed upon exchanging -COOMe for -CONHMe in the inhibitor, resulting in the net addition of one hydrogen bond interaction between each of the two -NH- groups and the HIV Protease backbone (Gly 48/148). The X-ray crystal structures of 43 and of 48 have been determined (Figures 5 and 6), revealing the binding mode of these inhibitors which will aid further design.

Figures