Antiviral Drugs: From Basic Discovery Through Clinical by Wieslaw M. Kazmierski

By Wieslaw M. Kazmierski

This publication makes a speciality of new small molecule techniques to wrestle viral infections. The chapters describe the invention and improvement from bench during the medical institution of quite recently-approved antiviral medicines and compounds in complicated scientific improvement. prepared through a pandemic (such as HIV, HCV, RSV, influenza, HBV and CMV) and written through most sensible educational and business professionals within the box, the e-book presents a distinct chance to review, comprehend and practice discovery and improvement rules and studying with out the necessity for someone to investigate, examine and synthesize all sizeable sourcing references.  issues exhibit demanding situations and strategies of matters encountered, offering tremendous event accrued over decades of study that may be relatively necessary to uncomplicated and bench scientists in addition to clinicians as they proceed getting to know and constructing new medicinal drugs and cures.

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From a drug design perspective, the effort sought to establish additional favorable contacts between the inhibitor and protease residues Arg8, Phe153, Gly148, and Gly149 located at the periphery of the S1 pocket [4]. 8 nM. Replacing the two valine residues with tert-Leu resulted in CGP-75355 (4), which showed Antiviral Drugs: From Basic Discovery Through Clinical Trials, First Edition. Edited by Wieslaw M. Kazmierski. © 2011 John Wiley & Sons, Inc. Published 2011 by John Wiley & Sons, Inc. 3 P1: TIX/XYZ JWBS061-01 P2: ABC JWBS061-Kazmierski 4 May 24, 2011 16:56 Printer Name: Yet to Come DISCOVERY AND DEVELOPMENT OF ATAZANAVIR H3CO2C H N N H O O OH N H N N H CO2CH2CH3 H3CO2C N H N O Ph O OH H N H N N H CO2CH2CH3 Ph 2 1 H3COC N H O OH H N N O H N N H COCH3 Ph 3 CGP-53820 N H3CO2C H N N H O O OH H N N N H CO2CH 3 H3CO2C H N N H O O OH N N H H N CO2CH 3 Ph Ph 4 (CGP-75355) SCHEME 1 5 Atazanavir (CGP-73547, BM S-262632) Discovery of atazanavir.

Clinical Trials in Antiretroviral-Naive Patients Study AI424-007 [17] was a 48-week dose-ranging phase II study comparing the safety and efficacy of atazanavir in doses of 200, 400, and 500 mg once daily to nelfinavir 750 mg three times a day in combination with didanosine and stavudine in 420 antiretroviral naive patients. The study was blinded to atazanavir dose but included an open-label comparison to nelfinavir. Subjects received atazanavir monotherapy for 2 weeks followed by the combination regimen for 46 weeks.

Clinical signs, considered to be agonal, were present just prior to or concomitant with death. Nonspecific clinical signs were also observed after dosing in surviving animals at high doses. Atazanavir was well tolerated in mice up to 400 mg/kg. In rats, the minimal lethal dose was greater than 1600 mg/kg. The greater sensitivity of mice to the acute effects of atazanavir compared to rats may be related to higher systemic exposure to atazanavir, as demonstrated in subsequent toxicity studies [9].

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