The Development of Cyclic Sulfolanes as Novel and High-Affinity P2 Ligands for HIV-1 Protease Inhibitors

• Published in: Journal of medicinal chemistry Vol. 37; no. 8; pp. 1177 - 1188
• Main Authors: Ghosh, Arun K, Lee, Hee Yoon, Thompson, Wayne J, Culberson, Chris, Holloway, M. Katharine, McKee, Sean P, Munson, Peter M, Duong, Tien T, Smith, Anthony M
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.04.1994
• Subjects: AIDS/HIV; Antiviral Agents - chemical synthesis; Binding Sites; Chemistry; Cyclization; Cyclopentanes - chemistry; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms; HIV Protease - metabolism; HIV Protease Inhibitors - chemical synthesis; HIV Protease Inhibitors - metabolism; HIV Protease Inhibitors - pharmacology; HIV-1 - drug effects; HIV-1 - enzymology; Isoquinolines - chemical synthesis; Isoquinolines - chemistry; Isoquinolines - metabolism; Isoquinolines - pharmacology; Models, Molecular; Molecular Conformation; Molecular Structure; Organic chemistry; Piperidines - chemistry; Preparations and properties; Quinolines - chemistry; Quinolines - pharmacology; Saquinavir; Structure-Activity Relationship; Thiophenes - chemical synthesis; Thiophenes - metabolism; Thiophenes - pharmacology; Chemical rearrangement; Five membered ring; Organic carbonate; Sulfone; HIV-1 virus; Nitrogen heterocycle; Sharpless epoxidation; Retroviridae; Enzyme inhibitor; In vitro; Biological activity; Virus; Sulfur heterocycle; Bicyclic compound; Lentivirinae; Antiviral; Human immunodeficiency virus
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00034a016

Design and synthesis of a novel series of protease inhibitors incorporating conformationally constrained cyclic ligands for the S2-substrate binding site of HIV-1 protease is described. We recently reported urethanes of 3-tetrahydrofuranyl as P2 ligands for HIV-1 protease inhibitors. Subsequently, we have found that the urethane of 3(S)-hydroxysulfolane further increased the in vitro potency of these inhibitors. Furthermore, introduction of a small 2-alkyl group cis to the 3-hydroxyl group of either heterocyclic system further enhanced enzyme affinity. The cis-2-isopropyl group thus far offered optimum enhancement of the inhibitory properties. This led to the discovery of inhibitor 43 (IC50 3.5 nM, CIC95 50 +/- 14 nM) of comparable in vitro antiviral potency to the current clinical candidate 1 (Ro 31-8959) but of reduced molecular weight due to the exclusion of the P3 quinoline ligand. Also, it has been demonstrated that the octahydropyrindene derivative 34 is an effective replacement of the P1' decahydroisoquinoline derivative.