title: Synthesis, X-ray analysis, and biological evaluation of a new class of stereopure lactam-based HIV-1 protease inhibitors.
abstract: In an effort to identify a new class of druglike HIV-1 protease inhibitors, four different stereopure β-hydroxy γ-lactam-containing inhibitors have been synthesized, biologically evaluated, and cocrystallized. The impact of the tether length of the central spacer (two or three carbons) was also investigated. A compound with a shorter tether and (3R,4S) absolute configuration exhibited high activity with a K(i) of 2.1 nM and an EC(50) of 0.64 μM. Further optimization by decoration of the P1' side chain furnished an even more potent HIV-1 protease inhibitor (K(i) = 0.8 nM, EC(50) = 0.04 μM). According to X-ray analysis, the new class of inhibitors did not fully succeed in forming two symmetric hydrogen bonds to the catalytic aspartates. The crystal structures of the complexes further explain the difference in potency between the shorter inhibitors (two-carbon spacer) and the longer inhibitors (three-carbon spacer).
authors.affiliation: Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, BMC, Uppsala University, P.O. Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Xiongyu
authors.initials: X
authors.lastname: Wu
authors.forename: Per
authors.initials: P
authors.lastname: Ohrngren
authors.forename: Advait A
authors.initials: AA
authors.lastname: Joshi
authors.forename: Alejandro
authors.initials: A
authors.lastname: Trejos
authors.forename: Magnus
authors.initials: M
authors.lastname: Persson
authors.forename: Riina K
authors.initials: RK
authors.lastname: Arvela
authors.forename: Hans
authors.initials: H
authors.lastname: Wallberg
authors.forename: Lotta
authors.initials: L
authors.lastname: Vrang
authors.forename: Asa
authors.initials: A
authors.lastname: Rosenquist
authors.forename: Bertil B
authors.initials: BB
authors.lastname: Samuelsson
authors.forename: Johan
authors.initials: J
authors.lastname: Unge
authors.forename: Mats
authors.initials: M
authors.lastname: Larhed
mesh_terms: D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D018360:Crystallography, X-Ray; D016333:HIV Protease / Q000737:chemistry* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007769:Lactams / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D017320:HIV Protease Inhibitors; D007769:Lactams; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1