Hydroxyethylene Sulfones as a New Scaffold To Address Aspartic Proteases:  Design, Synthesis, and Structural Characterization

• Published in: Journal of medicinal chemistry Vol. 48; no. 21; pp. 6607 - 6619
• Main Authors: Specker, Edgar, Böttcher, Jark, Heine, Andreas, Sotriffer, Christoph A, Lilie, Hauke, Schoop, Andreas, Müller, Gerhard, Griebenow, Nils, Klebe, Gerhard
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 20.10.2005; Amer Chemical Soc
• Subjects: Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Binding Sites; Biological and medical sciences; Chemistry, Medicinal; Crystallography, X-Ray; Ethylenes - chemical synthesis; Ethylenes - chemistry; HIV Protease - chemistry; Human immunodeficiency virus 1; Kinetics; Life Sciences & Biomedicine; Medical sciences; Models, Molecular; Molecular Structure; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Science & Technology; Stereoisomerism; Structure-Activity Relationship; Sulfones - chemical synthesis; Sulfones - chemistry; SECRETASE; POTENT; ENZYME; PEPSTATIN; PURIFICATION; AUTOMATED DOCKING; HIV-1 PROTEASE; INHIBITORS; DIPEPTIDE ANALOGS; CATHEPSIN-D; Enantioselectivity; Sulfone; HIV-1 virus; Modeling; Structure activity relation; Enantiomer; Molecular model; Binding mode; Antiviral; Bromine Organic compounds; Secondary alcohol; Chemical synthesis; Enzyme; Aliphatic compound; Benzene derivatives; Retroviridae; Enzyme inhibitor; Inhibitor enzyme complex; Lentivirus; X ray diffraction; In vitro; Virus; Peptidases; Hydrolases; Carboxamide; Fluorine Organic compounds; Human immunodeficiency virus; Protease inhibitor; Crystalline structure
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm050224y

Hydroxyethylene sulfones were developed as novel scaffolds against aspartyl proteases. A diastereoselective synthesis has been established to introduce the required side chain decoration with desired stereochemistry. Depending on the substitution of the hydroxyethylene sulfone core, micro- to submicromolar inhibition of HIV-1 protease is achieved for the S-configuration at P1 and R-configuration at the hydroxy-group-bearing backbone atom. This stereochemical preference is consistent with the S,R configuration of amprenavir. The racemic mixture of the most potent derivative (K i = 80 nM) was separated by chiral HPLC, revealing the S,R,S-enantiomer to be more active (K i = 45 nM). Docking studies suggested this isomer as the more active one. The subsequently determined crystal structure with HIV-1 protease, cocrystallized from a racemic mixture, exclusively reveals the S,R,S-enantiomer accommodated to the binding pocket. The transition state mimicking hydroxy group of the inhibitor is centered between both catalytic aspartates, while either its carbonyl or sulfonyl group forms H-bonds to the structurally conserved water mediating interactions between ligand and Ile50NH/Ile50NH‘ of both flaps. Biological testing of the stereoisomeric hydroxyethylene sulfones against cathepsin D and β-secretase did not reveal significant inhibition. Most likely, the latter proteases require inverted configuration at the hydroxy group.