title: A minimally cytotoxic CD4 mimic as an HIV entry inhibitor.
abstract: Several CD4 mimics have been reported as HIV-1 entry inhibitors which can block the interaction between the viral envelope glycoprotein gp120 and the cell surface protein CD4. We previously found a lead compound 2 (YYA-021) with high anti-HIV activity and low cytotoxicity. Pharmacokinetic analysis however showed compound 2 to have wide tissue distribution and relatively high distribution volumes in rats and rhesus macaques. In the present study we searched for more hydrophilic CD4 mimics with a view to reducing tissue distribution. A new compound (5) with a 1,3-benzodioxolyl moiety was found to have relatively high anti-HIV activity and no significant cytotoxicity. Compound 5 is more hydrophilic than compound 2 and the pharmacokinetics of the intravenous administration of compound 5 in a rhesus macaque showed that compound 5 has lower tissue distribution than compound 2, suggesting that compound 5 possesses a better profile.
authors.affiliation: Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo 101-0062, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Mizuguchi
authors.affiliation: AIDS Research Center, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo 162-8640, Japan.
authors.forename: Shigeyoshi
authors.initials: S
authors.lastname: Harada
authors.affiliation: Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Miura
authors.affiliation: Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo 101-0062, Japan.
authors.forename: Nami
authors.initials: N
authors.lastname: Ohashi
authors.affiliation: Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo 101-0062, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Narumi
authors.affiliation: Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Mori
authors.affiliation: Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo 101-0062, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Irahara
authors.affiliation: Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo 101-0062, Japan; Pharmaceutical Department, Keio University Hospital, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo 101-0062, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Nomura
authors.affiliation: Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan.
authors.forename: Shuzo
authors.initials: S
authors.lastname: Matsushita
authors.affiliation: AIDS Research Center, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo 162-8640, Japan. Electronic address: ykazu@nih.go.jp.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Yoshimura
authors.affiliation: Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo 101-0062, Japan. Electronic address: tamamura.mr@tmd.ac.jp.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Tamamura
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000737:chemistry* / Q000494:pharmacology*; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D023581:HIV Fusion Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D015658:HIV Infections / Q000188:drug therapy; D015497:HIV-1 / Q000187:drug effects*; D008253:Macaca mulatta; D062105:Molecular Docking Simulation; D010072:Oxamic Acid / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D010880:Piperidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats
chemical_list: D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D023581:HIV Fusion Inhibitors; D010880:Piperidines; C000591642:YYA-021; D010072:Oxamic Acid
keywords: CD4 mimic; Conformational change in gp120; HIV entry inhibitor; Pharmacokinetics