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Antimicrobial Agents and Chemotherapy, June 2005, p. 2267-2275, Vol. 49, No. 6
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.6.2267-2275.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

In Vitro Antiviral Activity and Single-Dose Pharmacokinetics in Humans of a Novel, Orally Bioavailable Inhibitor of Human Rhinovirus 3C Protease

Amy K. Patick,* Mary A. Brothers, Fausto Maldonado, Susan Binford, Oscar Maldonado, Shella Fuhrman, Annkatrin Petersen, George J. Smith III, Leora S. Zalman, Leigh Ann Burns-Naas, and Jonathan Q. Tran

Pfizer Global Research and Development, 10777 Science Center Drive, San Diego, California 92121

Received 27 October 2004/ Returned for modification 28 December 2004/ Accepted 27 January 2005

(E)-(S)-4-((S)-2-{3-[(5-methyl-isoxazole-3-carbonyl)-amino]-2-oxo-2H-pyridin-1-yl}-pent-4-ynoylamino)-5-((S)-2-oxo-pyrrolidin-3-yl)-pent-2-enoic acid ethyl ester (Compound 1) is a novel, irreversible inhibitor of human rhinovirus (HRV) 3C protease {inactivation rate constant (Kobs/[I]) of 223,000 M–1s–1}. In cell-based assays, Compound 1 was active against all HRV serotypes (35 of 35), HRV clinical isolates (5 of 5), and related picornaviruses (8 of 8) tested with mean 50% effective concentration (EC50) values of 50 nM (range, 14 to 122 nM), 77 nM (range, 72 to 89 nM), and 75 nM (range, 7 to 249 nM), respectively. Compound 1 inhibited HRV 3C-mediated polyprotein processing in infected cells in a concentration-dependent manner, providing direct confirmation that the cell-based antiviral activity is due to inhibition of 3C protease. In vitro and in vivo nonclinical safety studies showed Compound 1 to be without adverse effects at maximum achievable doses. Single oral doses of Compound 1 up to 2,000 mg in healthy volunteers were found to be safe and well tolerated in a phase I-ascending, single-dose study. Compound 1 estimated free observed maximum concentration in plasma (Cmax) for 500-, 1,000-, and 2,000-mg doses were higher than the protein binding-corrected EC50 required to inhibit 80% of the HRV serotypes tested. Treatment of HRV 52-infected cells with one to five 2-h pulses of 150 nM Compound 1 (corresponding to the Cmax at the 500-mg dose) was sufficient to effect a significant reduction in viral replication. These experiments highlight Compound 1 as a potent, orally bioavailable, irreversible inhibitor of HRV 3C protease and provide data that suggest that Cmax rather than the Cmin might be the key variable predicting clinical efficacy.

* Corresponding author. Mailing address: Department of Virology, Pfizer Global Research and Development, 10777 Science Center Drive, San Diego, CA 92121. Phone: (858) 622-3117. Fax: (858) 678-8182. E-mail: amy.patick{at}pfizer.com.

Antimicrobial Agents and Chemotherapy, June 2005, p. 2267-2275, Vol. 49, No. 6
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.6.2267-2275.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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  • Binford, S. L., Weady, P. T., Maldonado, F., Brothers, M. A., Matthews, D. A., Patick, A. K. (2007). In Vitro Resistance Study of Rupintrivir, a Novel Inhibitor of Human Rhinovirus 3C Protease. Antimicrob. Agents Chemother. 51: 4366-4373 [Abstract] [Full Text]  


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