Potent inhibitors of the HIV-1 protease incorporating cyclic urea P1-P2 scaffold

Bioorg Med Chem Lett. 2004 Nov 15;14(22):5685-7. doi: 10.1016/j.bmcl.2004.08.038.

Abstract

We have developed synthetic approaches to novel analogues of 2-imidazolidinone scaffold 2, which was found to be an effective P1-P2 mimetic in HIV-1 protease inhibitor 4. This enabled a rapid synthesis of analogues of 4 and subsequently allowed us to evaluate and rationalize the SAR. Accordingly, trans relationship of P1 and P2 substituents in the P1-P2 mimetic, as found in a related 2-pyrrolidone-based scaffold 1, was found necessary for high potency against HIV-1 protease. Results of this study provided further rationale towards subsequent optimization of 2-pyrrolidone-based lead 3, which led us to potent and drug-like HIV-1 protease inhibitors described in a follow-on report (Bioorg. Med. Chem. Lett. 2004, 14, in press. ).

MeSH terms

  • Cyclization
  • Drug Design
  • HIV Protease / drug effects*
  • HIV Protease Inhibitors / chemical synthesis*
  • HIV Protease Inhibitors / chemistry
  • HIV Protease Inhibitors / pharmacology*
  • Heterocyclic Compounds / chemical synthesis
  • Heterocyclic Compounds / chemistry
  • Heterocyclic Compounds / pharmacology
  • Imidazolidines / chemical synthesis
  • Molecular Conformation
  • Structure-Activity Relationship
  • Urea* / analogs & derivatives
  • Urea* / chemical synthesis
  • Urea* / pharmacology

Substances

  • HIV Protease Inhibitors
  • Heterocyclic Compounds
  • Imidazolidines
  • Urea
  • HIV Protease