期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 5, 期 4, 页码 422-427出版社
AMER CHEMICAL SOC
DOI: 10.1021/ml500002n
关键词
HIV Integrase; allosteric inhibitor; LTR DNA 3 '-processing; NCINI
An assay recapitulating the 3' processing activity of HIV-1 integrase (IN) was used to screen the Boehringer Ingelheim compound collection. Hit-to-lead and lead optimization beginning with compound 1 established the importance of the C3 and C4 substituent to antiviral potency against viruses with different aa124/aa125 variants of IN. The importance of the C7 position on the serum shifted potency was established. Introduction of a quinoline substituent at the C4 position provided a balance of potency and metabolic stability. Combination of these findings ultimately led to the discovery of compound 26 (BI 224436), the first NCINI to advance into a phase Ia clinical trial.
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