title: Probing Lipophilic Adamantyl Group as the P1-Ligand for HIV-1 Protease Inhibitors: Design, Synthesis, Protein X-ray Structural Studies, and Biological Evaluation.
abstract: A series of potent HIV-1 protease inhibitors with a lipophilic adamantyl P1 ligand have been designed, synthesized, and evaluated. We have developed an enantioselective synthesis of adamantane-derived hydroxyethylamine isosteres utilizing Sharpless asymmetric epoxidation as the key step. Various inhibitors incorporating P1-adamantylmethyl in combination with P2 ligands such as 3-(R)-THF, 3-(S)-THF, bis-THF, and THF-THP were examined. The S1' pocket was also probed with phenyl and phenylmethyl ligands. Inhibitor 15d, with an isobutyl P1' ligand and a bis-THF P2 ligand, proved to be the most potent of the series. The cLogP value of inhibitor 15d is improved compared to inhibitor 2 with a phenylmethyl P1-ligand. X-ray structural studies of 15d, 15h, and 15i with HIV-1 protease complexes revealed molecular insight into the inhibitor-protein interaction.
authors.affiliation: Department of Chemistry and Department of Medicinal Chemistry, Purdue University , 560 Oval Drive, West Lafayette, Indiana 47907, United States.
authors.forename: Arun K
authors.initials: AK
authors.lastname: Ghosh
authors.affiliation: Department of Chemistry and Department of Medicinal Chemistry, Purdue University , 560 Oval Drive, West Lafayette, Indiana 47907, United States.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Osswald
authors.affiliation: Department of Chemistry and Department of Medicinal Chemistry, Purdue University , 560 Oval Drive, West Lafayette, Indiana 47907, United States.
authors.forename: Kristof
authors.initials: K
authors.lastname: Glauninger
authors.affiliation: Department of Biology, Molecular Basis of Disease, Georgia State University , Atlanta, Georgia 30303, United States.
authors.forename: Johnson
authors.initials: J
authors.lastname: Agniswamy
authors.affiliation: Department of Biology, Molecular Basis of Disease, Georgia State University , Atlanta, Georgia 30303, United States.
authors.forename: Yuan-Fang
authors.initials: YF
authors.lastname: Wang
authors.affiliation: Departments of Infectious Diseases and Hematology, Kumamoto University Graduate School of Medical Sciences , Kumamoto 860-8556, Japan.|Center for Clinical Sciences, National Center for Global Health and Medicine , Tokyo 162-8655, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Hayashi
authors.affiliation: Departments of Infectious Diseases and Hematology, Kumamoto University Graduate School of Medical Sciences , Kumamoto 860-8556, Japan.|Department of Medical Technology, Kumamoto Health Science University , Kumamoto 861-5598, Japan.|Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors.forename: Manabu
authors.initials: M
authors.lastname: Aoki
authors.affiliation: Department of Biology, Molecular Basis of Disease, Georgia State University , Atlanta, Georgia 30303, United States.
authors.forename: Irene T
authors.initials: IT
authors.lastname: Weber
authors.affiliation: Departments of Infectious Diseases and Hematology, Kumamoto University Graduate School of Medical Sciences , Kumamoto 860-8556, Japan.|Center for Clinical Sciences, National Center for Global Health and Medicine , Tokyo 162-8655, Japan.|Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mitsuya
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D016333:HIV Protease / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D017320:HIV Protease Inhibitors; D008024:Ligands; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1; D000218:Adamantane