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Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect (2010)

M. Gao ; R. E. Nettles ; M. Belema ; [et al.]

Nature Publishing Group (NPG)

In: Nature. 465(7294): 96-100. doi: 10.1038/nature08960.

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Publication Date: 2010-04-23

Description: The worldwide prevalence of chronic hepatitis C virus (HCV) infection is estimated to be approaching 200 million people. Current therapy relies upon a combination of pegylated interferon-alpha and ribavirin, a poorly tolerated regimen typically associated with less than 50% sustained virological response rate in those infected with genotype 1 virus. The development of direct-acting antiviral agents to treat HCV has focused predominantly on inhibitors of the viral enzymes NS3 protease and the RNA-dependent RNA polymerase NS5B. Here we describe the profile of BMS-790052, a small molecule inhibitor of the HCV NS5A protein that exhibits picomolar half-maximum effective concentrations (EC(50)) towards replicons expressing a broad range of HCV genotypes and the JFH-1 genotype 2a infectious virus in cell culture. In a phase I clinical trial in patients chronically infected with HCV, administration of a single 100-mg dose of BMS-790052 was associated with a 3.3 log(10) reduction in mean viral load measured 24 h post-dose that was sustained for an additional 120 h in two patients infected with genotype 1b virus. Genotypic analysis of samples taken at baseline, 24 and 144 h post-dose revealed that the major HCV variants observed had substitutions at amino-acid positions identified using the in vitro replicon system. These results provide the first clinical validation of an inhibitor of HCV NS5A, a protein with no known enzymatic function, as an approach to the suppression of virus replication that offers potential as part of a therapeutic regimen based on combinations of HCV inhibitors.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gao, Min -- Nettles, Richard E -- Belema, Makonen -- Snyder, Lawrence B -- Nguyen, Van N -- Fridell, Robert A -- Serrano-Wu, Michael H -- Langley, David R -- Sun, Jin-Hua -- O'Boyle, Donald R 2nd -- Lemm, Julie A -- Wang, Chunfu -- Knipe, Jay O -- Chien, Caly -- Colonno, Richard J -- Grasela, Dennis M -- Meanwell, Nicholas A -- Hamann, Lawrence G -- England -- Nature. 2010 May 6;465(7294):96-100. doi: 10.1038/nature08960. Epub 2010 Apr 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20410884" target="_blank"〉PubMed〈/a〉

Keywords: Adolescent ; Adult ; Animals ; Antiviral Agents/blood/chemistry/*pharmacology/therapeutic use ; Cell Line ; Cercopithecus aethiops ; Drug Resistance, Viral ; Female ; Genotype ; HeLa Cells ; Hepacivirus/*drug effects ; Hepatitis C/drug therapy/virology ; Humans ; Imidazoles/blood/chemistry/*pharmacology ; Inhibitory Concentration 50 ; Male ; Middle Aged ; Time Factors ; Vero Cells ; Viral Load/drug effects ; Viral Nonstructural Proteins/*antagonists & inhibitors ; Young Adult

Print ISSN: 0028-0836

Electronic ISSN: 1476-4687

Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics

Published by Nature Publishing Group (NPG)

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Fosinopril pharmacokinetics and pharmacodynamics in chronic ambulatory peritoneal dialysis patients (1991)

Gehr, T. W. B. ; Sica, D. A. ; Grasela, D. M. ; [et al.]

Springer

European journal of clinical pharmacology 41 (1991), S. 165-169

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ISSN: 1432-1041

Keywords: Fosinopril ; fosinoprilat ; CAPD ; ACE-inhibitor ; pharmacokinetics ; pharmacodynamics ; peritoneal dialysis

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology , Medicine

Notes: Summary The pharmacokinetics and pharmacodynamics of fosinoprilat, the diacid of fosinopril sodium, a new angiotensin-converting enzyme (ACE) inhibitor, were investigated after the oral administration of 10 mg of fosinopril sodium to 6 chronic ambulatory peritoneal dialysis (CAPD) patients. The results from 1 patient are reported separately because of the presence of concomitant liver dysfunction. The mean t1/2, Cmax, tmax, and AUC values for 5 of the CAPD patients were 19.5 h, 202 ng·ml−1, 4.8 h, and 3.19 μg·h·ml−1, respectively. Values for 1 CAPD patient with liver dysfunction were t1/2 of 65.4 h, Cmax of 182 ng·ml−1, tmax of 9 h, and AUC of 18.1 μg·h·ml−1. Peritoneal clearance of fosinoprilat was negligible, ranging from 0.07 to 0.23 ml·min−1. Serum ACE activity remained significantly suppressed at 24 and 48 h after fosinopril sodium administration with mean decreases from baseline of 94.2% and 70.6%, respectively. ACE activity was suppressed to an even greater degree in the patient with liver dysfunction, remaining 97% inhibited 72 h after drug administration. Plasma renin activity (PRA) increased and plasma aldosterone concentrations decreased following drug administration. Mean arterial pressure did not change appreciably throughout the study. Dosage reductions may not be necessary in the majority of dialysis patients.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF00265911

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The pharmacokinetics and pharmacodynamics of fosinopril in haemodialysis patients (1993)

Gehr, T. W. B. ; Sica, D. A. ; Grasela, D. M. ; [et al.]

Springer

European journal of clinical pharmacology 45 (1993), S. 431-436

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ISSN: 1432-1041

Keywords: Fosinopril ; ACE inhibitors ; haemodialysis ; pharmacokinetics ; pharmacokinetics-pharmacodynamics

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology , Medicine

Notes: Summary The pharmacokinetics and pharmacodynamics of fosinoprilat, the diacid of fosinopril sodium (a new angiotensin-converting enzyme (ACE) inhibitor), were investigated in six haemodialysis patients. Intravenous 14C-fosinoprilat (7.5 mg), oral 14C-fosinopril sodium (10 mg) and oral fosinopril sodium (10 mg) were administered in an open-label, randomized study. Mean maximum concentration (Cmax), clearance (CL), volume of distribution at steady-state (Vss), mean residence time (MRTiv), and t1/2 values after IV administration of 14C-fosinoprilat were 2,042 μg·ml−1, 11.3 ml·min−1, 11.01, 16.3 h and 28.3 h, respectively. Following oral administration of 14C-fosinopril, mean Cmax, time to maximum plasma concentration (tmax), and fosinoprilat bioavailability values were 197 ng·ml−1, 5.2 h and 29.2 %. Para-hydroxy fosinoprilat and fosinoprilat glucuronide comprised approximately 15 % and 2 % of radioactivity recovered in faeces. Four hours of haemodialysis only cleared approximately 1.5 % of the administered dose. The maximum effect (Emax) model was fitted to the percentage inhibition of serum ACE activity vs. fosinoprilat concentration data in three patients. Emax ranged from 95.3 to 102.5 %, and IC50 (the fosinoprilat concentration required to produce 50 % of Emax) ranged from 2.6 to 4.2 ng·ml−1. Pharmacokinetic variables of the patients were similar to those in patients with moderate to severe renal dysfunction. Dosage modifications or supplemental dosing following dialysis are unnecessary.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF00315514

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