부산대학교 도서관

Theredesign of the previously reported thiophene-3-yl-methyl ureaseries, as a result of potential cardiotoxicity, was successfullyaccomplished, resulting in the identification of a novel potent seriesof CCR5 antagonists containing the imidazolidinylpiperidinyl scaffold.The main redesign criteria were to reduce the number of rotatablebonds and to maintain an acceptable lipophilicity to mitigate hERGinhibition. The structure–activity relationship (SAR) thatwas developed was used to identify compounds with the best pharmacologicalprofile to inhibit HIV-1. As a result, five advanced compounds, 6d, 6e, 6i, 6h, and 6k, were further evaluated for receptor selectivity, antiviralactivity against CCR5 using (R5) HIV-1 clinical isolates, and in vitroand in vivo safety. On the basis of these results, 6dand 6hwere selected for further development. [ABSTRACT FROM AUTHOR]