CD4 mimics as HIV entry inhibitors: Lead optimization studies of the aromatic substituents |
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Authors: | Tetsuo Narumi Hiroshi Arai Kazuhisa Yoshimura Shigeyoshi Harada Yuki Hirota Nami Ohashi Chie Hashimoto Wataru Nomura Shuzo Matsushita Hirokazu Tamamura |
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Institution: | 1. Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo 101-0062, Japan;2. Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan;3. AIDS Research Center, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo 162-8640, Japan |
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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. |
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