Résumé:
Small molecules that exhibit broad-spectrum enteroviral inhibitory activity by targeting viral replication proteins are highly desired in antiviral drug discovery studies. To discover new human rhinovirus (hRV) inhibitors, we performed a high-throughput screening of 100,000 compounds from the Korea Chemical Bank library. This search led to identification of two phosphatidylinositol-4-kinase III beta (PI4KIII beta) inhibitors having the pyrazolo-pyrimidine core structure, which display moderate anti-rhinoviral activity along with mild cytotoxicity. The results of a study aimed at optimizing the activity of the hit compounds showed that the pyrazolo-pyrimidine derivative <bold>6f</bold> exhibits the highest activity (EC50 = 0.044, 0.066, and 0.083 mu M for hRV-B14, hRV-A16, and hRV-A21, respectively) and moderate toxicity (CC50 = 31.38 mu M). Furthermore, <bold>6f</bold> has broad-spectrum activities against various hRVs, coxsackieviruses and other enteroviruses, such as EV-A71, EV-D68. An assessment of kinase inhibition potencies demonstrated that <bold>6f</bold> possesses a high and selective kinase inhibition activity against PI4KIII beta (IC50 value of 0.057 mu M) and not against PI4KIII alpha (>10 mu M). Moreover, <bold>6f</bold> exhibits modest hepatic stability (46.9 and 55.3 % remaining after 30 min in mouse and human liver microsomes, respectively). Finally, an in vivo study demonstrated that <bold>6f</bold> possesses a desirable pharmacokinetic profile reflected in low systemic clearance (0.48 L center dot h(-1) kg(-1)) and modest oral bioavailability (52.4 %). Hence, <bold>6f</bold> (KR-26549) appears to be an ideal lead for the development of new antiviral drugs.
