title: CD4 mimics as HIV entry inhibitors: lead optimization studies of the aromatic substituents.
abstract: Several CD4 mimics have been reported as HIV-1 entry inhibitors that can intervene in the interaction between a viral envelope glycoprotein gp120 and a cell surface protein CD4. Our previous SAR studies led to a finding of a highly potent analogue 3 with bulky hydrophobic groups on a piperidine moiety. In the present study, the aromatic ring of 3 was modified systematically in an attempt to improve its antiviral activity and CD4 mimicry which induces the conformational changes in gp120 that can render the envelope more sensitive to neutralizing antibodies. Biological assays of the synthetic compounds revealed that the introduction of a fluorine group as a meta-substituent of the aromatic ring caused an increase of anti-HIV activity and an enhancement of a CD4 mimicry, and led to a novel compound 13a that showed twice as potent anti-HIV activity compared to 3 and a substantial increase in a CD4 mimicry even at lower concentrations.
authors.affiliation: Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo 101-0062, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Narumi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Arai
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Yoshimura
authors.forename: Shigeyoshi
authors.initials: S
authors.lastname: Harada
authors.forename: Yuki
authors.initials: Y
authors.lastname: Hirota
authors.forename: Nami
authors.initials: N
authors.lastname: Ohashi
authors.forename: Chie
authors.initials: C
authors.lastname: Hashimoto
authors.forename: Wataru
authors.initials: W
authors.lastname: Nomura
authors.forename: Shuzo
authors.initials: S
authors.lastname: Matsushita
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Tamamura
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D040761:Biomimetic Materials / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015704:CD4 Antigens / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D015699:HIV Envelope Protein gp120 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120