Design, Synthesis, Protein−Ligand X-ray Structure, and Biological Evaluation of a Series of Novel Macrocyclic Human Immunodeficiency Virus-1 Protease Inhibitors to Combat Drug Resistance

• Published in: Journal of medicinal chemistry 2009-12, Vol.52 (23), p.7689-7705
• Main Authors: Ghosh, Arun K, Kulkarni, Sarang, Anderson, David D, Hong, Lin, Baldridge, Abigail, Wang, Yuan-Fang, Chumanevich, Alexander A, Kovalevsky, Andrey Y, Tojo, Yasushi, Amano, Masayuki, Koh, Yasuhiro, Tang, Jordan, Weber, Irene T, Mitsuya, Hiroaki
• Format: Article
• Language: English
• Subjects: 08 HYDROGEN; AIDS VIRUS; Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; BONDING; Cell Line; Crystallography, X-Ray; DESIGN; Drug Design; Drug Resistance, Viral - drug effects; ENZYMES; EVALUATION; HIV Protease - chemistry; HIV Protease - genetics; HIV Protease - metabolism; HIV Protease Inhibitors - chemical synthesis; HIV Protease Inhibitors - chemistry; HIV Protease Inhibitors - pharmacology; HIV-1 - drug effects; HIV-1 - enzymology; HIV-1 - genetics; Humans; HYDROGEN; Ligands; Macrocyclic Compounds - chemical synthesis; Macrocyclic Compounds - chemistry; Macrocyclic Compounds - pharmacology; Medical sciences; Models, Molecular; Molecular Conformation; Mutation; Pharmacology. Drug treatments; PROTEINS; SYNTHESIS
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm900695w

The structure-based design, synthesis, and biological evaluation of a series of nonpeptidic macrocyclic HIV protease inhibitors are described. The inhibitors are designed to effectively fill in the hydrophobic pocket in the S1′−S2′ subsites and retain all major hydrogen bonding interactions with the protein backbone similar to darunavir (1) or inhibitor 2. The ring size, the effect of methyl substitution, and unsaturation within the macrocyclic ring structure were assessed. In general, cyclic inhibitors were significantly more potent than their acyclic homologues, saturated rings were less active than their unsaturated analogues and a preference for 10- and 13-membered macrocylic rings was revealed. The addition of methyl substituents resulted in a reduction of potency. Both inhibitors 14b and 14c exhibited marked enzyme inhibitory and antiviral activity, and they exerted potent activity against multidrug-resistant HIV-1 variants. Protein−ligand X-ray structures of inhibitors 2 and 14c provided critical molecular insights into the ligand-binding site interactions.