Inhibitors of HIV-1 attachment. Part 4: A study of the effect of piperazine substitution patterns on antiviral potency in the context of indole-based derivatives |
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| Authors: | Tao Wang John F Kadow Zhongxing Zhang Zhiwei Yin Qi Gao Dedong Wu Dawn DiGiugno Parker Zheng Yang Lisa Zadjura Brett A Robinson Yi-Fei Gong Wade S Blair Pei-Yong Shi Gregory Yamanaka Pin-Fang Lin Nicholas A Meanwell |
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| Institution: | 1. Department of Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States;2. Department of Analytical Research and Development, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States;3. Department of Pharmaceutics, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States;4. Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States;5. Department of Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States |
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| Abstract: | 4-Fluoro- and 4-methoxy-1-(4-benzoylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione (2 and 3, respectively) have been characterized as potent inhibitors of HIV-1 attachment that interfere with the interaction of viral gp120 with the host cell receptor CD4. As part of an effort to understand fundamental aspects of this pharmacophore, discovered originally using a high throughput cell-based screen, modification and substitution of the piperazine ring was examined in the context of compounds 6a–ah. The piperazine ring was shown to be a critical element of the HIV-1 attachment inhibiting pharmacophore, acting as a scaffold to deploy the indole glyoxamide and benzamide in a topographical relationship that complements the binding site on gp120. |
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