Single oral doses of Compound 1 up to 2,000 mg were safe and well tolerated in healthy volunteers, achieving plasma concentrations sufficient to inhibit human rhinovirus replication.
Compound 1 is a potent, orally bioavailable inhibitor of HRV 3C protease that is safe in healthy volunteers and achieves plasma concentrations sufficient for viral inhibition.
(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.
Patick et al. (Wed,) conducted a other in Healthy volunteers. Compound 1 was evaluated on Safety and tolerability. Single oral doses of Compound 1 up to 2,000 mg were safe and well tolerated in healthy volunteers, achieving plasma concentrations sufficient to inhibit human rhinovirus replication.