Pyrazolopyrimidines: Potent Inhibitors Targeting the Capsid of Rhino- and Enteroviruses

There are currently no drugs available for the treatment of enterovirus (EV)‐induced acute and chronic diseases such as the common cold, meningitis, encephalitis, pneumonia, and myocarditis with or without consecutive dilated cardiomyopathy. Here, we report the discovery and characterization of pyrazolopyrimidines, a well‐tolerated and potent class of novel EV inhibitors. The compounds inhibit the replication of a broad spectrum of EV in vitro with IC₅₀ values between 0.04 and 0.64 μM for viruses resistant to pleconaril, a known capsid‐binding inhibitor, without affecting cytochrome P450 enzyme activity. Using virological and genetics methods, the viral capsid was identified as the target of the most promising, orally bioavailable compound 3‐(4‐trifluoromethylphenyl)amino‐6‐phenylpyrazolo[3,4‐d]pyrimidine‐4‐amine (OBR‐5‐340). Its prophylactic as well as therapeutic application was proved for coxsackievirus B3‐induced chronic myocarditis in mice. The favorable pharmacokinetic, toxicological, and pharmacodynamics profile in mice renders OBR‐5‐340 a highly promising drug candidate, and the regulatory nonclinical program is ongoing.