1. Preclinical characterization of an intravenous coronavirus 3CL protease inhibitor for the potential treatment of COVID19.
- Author
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Boras B, Jones RM, Anson BJ, Arenson D, Aschenbrenner L, Bakowski MA, Beutler N, Binder J, Chen E, Eng H, Hammond H, Hammond J, Haupt RE, Hoffman R, Kadar EP, Kania R, Kimoto E, Kirkpatrick MG, Lanyon L, Lendy EK, Lillis JR, Logue J, Luthra SA, Ma C, Mason SW, McGrath ME, Noell S, Obach RS, O' Brien MN, O'Connor R, Ogilvie K, Owen D, Pettersson M, Reese MR, Rogers TF, Rosales R, Rossulek MI, Sathish JG, Shirai N, Steppan C, Ticehurst M, Updyke LW, Weston S, Zhu Y, White KM, García-Sastre A, Wang J, Chatterjee AK, Mesecar AD, Frieman MB, Anderson AS, and Allerton C
- Subjects
- Adenosine Monophosphate administration & dosage, Adenosine Monophosphate adverse effects, Adenosine Monophosphate analogs & derivatives, Adenosine Monophosphate pharmacokinetics, Alanine administration & dosage, Alanine adverse effects, Alanine analogs & derivatives, Alanine pharmacokinetics, Animals, COVID-19 virology, Chlorocebus aethiops, Coronavirus 229E, Human drug effects, Coronavirus 229E, Human enzymology, Coronavirus Protease Inhibitors adverse effects, Coronavirus Protease Inhibitors pharmacokinetics, Disease Models, Animal, Drug Design, Drug Synergism, Drug Therapy, Combination, HeLa Cells, Humans, Indoles adverse effects, Indoles pharmacokinetics, Infusions, Intravenous, Leucine adverse effects, Leucine pharmacokinetics, Mice, Pyrrolidinones adverse effects, Pyrrolidinones pharmacokinetics, Severe acute respiratory syndrome-related coronavirus drug effects, Severe acute respiratory syndrome-related coronavirus enzymology, SARS-CoV-2 drug effects, SARS-CoV-2 enzymology, Vero Cells, Coronavirus 3C Proteases antagonists & inhibitors, Coronavirus Protease Inhibitors administration & dosage, Indoles administration & dosage, Leucine administration & dosage, Pyrrolidinones administration & dosage, COVID-19 Drug Treatment
- Abstract
COVID-19 caused by the SARS-CoV-2 virus has become a global pandemic. 3CL protease is a virally encoded protein that is essential across a broad spectrum of coronaviruses with no close human analogs. PF-00835231, a 3CL protease inhibitor, has exhibited potent in vitro antiviral activity against SARS-CoV-2 as a single agent. Here we report, the design and characterization of a phosphate prodrug PF-07304814 to enable the delivery and projected sustained systemic exposure in human of PF-00835231 to inhibit coronavirus family 3CL protease activity with selectivity over human host protease targets. Furthermore, we show that PF-00835231 has additive/synergistic activity in combination with remdesivir. We present the ADME, safety, in vitro, and in vivo antiviral activity data that supports the clinical evaluation of PF-07304814 as a potential COVID-19 treatment., (© 2021. The Author(s).)
- Published
- 2021
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