title: Pyrazolopyrimidines: Potent Inhibitors Targeting the Capsid of Rhino- and Enteroviruses.
abstract: 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.
authors.affiliation: A. N. Bach Institute of Biochemistry, Russian Academy of Sciences, Leninsky pr. 33, build. 2, Moscow 119071 (Russia).
authors.forename: Vadim A
authors.initials: VA
authors.lastname: Makarov
authors.affiliation: Virology & Antiviral Therapy, Jena University Hospital, Hans-Knöll-Str. 2, 07745 Jena (Germany).
authors.forename: Heike
authors.initials: H
authors.lastname: Braun
authors.affiliation: Virology & Antiviral Therapy, Jena University Hospital, Hans-Knöll-Str. 2, 07745 Jena (Germany).
authors.forename: Martina
authors.initials: M
authors.lastname: Richter
authors.affiliation: A. N. Bach Institute of Biochemistry, Russian Academy of Sciences, Leninsky pr. 33, build. 2, Moscow 119071 (Russia).
authors.forename: Olga B
authors.initials: OB
authors.lastname: Riabova
authors.affiliation: Center for Bioinformatics, University of Hamburg, Bundesstrasse 43, 20146 Hamburg (Germany).
authors.forename: Johannes
authors.initials: J
authors.lastname: Kirchmair
authors.affiliation: A. N. Bach Institute of Biochemistry, Russian Academy of Sciences, Leninsky pr. 33, build. 2, Moscow 119071 (Russia).
authors.forename: Elena S
authors.initials: ES
authors.lastname: Kazakova
authors.affiliation: Virology & Antiviral Therapy, Jena University Hospital, Hans-Knöll-Str. 2, 07745 Jena (Germany).
authors.forename: Nora
authors.initials: N
authors.lastname: Seidel
authors.affiliation: Virology & Antiviral Therapy, Jena University Hospital, Hans-Knöll-Str. 2, 07745 Jena (Germany).
authors.forename: Peter
authors.initials: P
authors.lastname: Wutzler
authors.affiliation: Virology & Antiviral Therapy, Jena University Hospital, Hans-Knöll-Str. 2, 07745 Jena (Germany). michaela.schmidtke@med.uni-jena.de.
authors.forename: Michaela
authors.initials: M
authors.lastname: Schmidtke
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002213:Capsid / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004770:Enterovirus / Q000187:drug effects*; D004769:Enterovirus Infections / Q000188:drug therapy*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D011720:Pyrazoles; D011743:Pyrimidines
keywords: antivirus agents; drug discovery; structure-property relationships; synthetic drugs; virology