Microwave-accelerated synthesis of P1'-extended HIV-1 protease inhibitors encompassing a tertiary alcohol in the transition-state mimicking scaffold

Jenny K Ekegren; Nina Ginman; Asa Johansson; Hans Wallberg; Mats Larhed; Bertil Samuelsson; Torsten Unge; Anders Hallberg

doi:10.1021/jm051239z

Microwave-accelerated synthesis of P1'-extended HIV-1 protease inhibitors encompassing a tertiary alcohol in the transition-state mimicking scaffold

J Med Chem. 2006 Mar 9;49(5):1828-32. doi: 10.1021/jm051239z.

Authors

Jenny K Ekegren¹, Nina Ginman, Asa Johansson, Hans Wallberg, Mats Larhed, Bertil Samuelsson, Torsten Unge, Anders Hallberg

Affiliation

¹ Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, BMC, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden.

PMID: 16509598
DOI: 10.1021/jm051239z

Abstract

Two series of P1'-extended HIV-1 protease inhibitors comprising a tertiary alcohol in the transition-state mimic exhibiting Ki values ranging from 2.1 to 93 nM have been synthesized. Microwave-accelerated palladium-catalyzed cross-couplings were utilized to rapidly optimize the P1' side chain. High cellular antiviral potencies were encountered when the P1' benzyl group was elongated with a 3- or 4-pyridyl substituent (EC50 = 0.18-0.22 microM). X-ray crystallographic data were obtained for three inhibitors cocrystallized with the enzyme.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alcohols / chemical synthesis*
Alcohols / chemistry
Alcohols / pharmacology
Binding Sites
Catalysis
Cell Line
Crystallography, X-Ray
HIV Protease / chemistry*
HIV Protease Inhibitors / chemical synthesis*
HIV Protease Inhibitors / chemistry
HIV Protease Inhibitors / pharmacology
HIV-1 / drug effects
Humans
Hydrogen Bonding
Indans / chemical synthesis*
Indans / chemistry
Indans / pharmacology
Microwaves
Molecular Mimicry
Palladium

Substances

Alcohols
HIV Protease Inhibitors
Indans
Palladium
HIV Protease