How Scientists Discover New Drugs for Viruses: Medicinal Chemistry and Drug Design (Hepatitis C)

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Total Synthesis	2022-05-19 14:35:57	24,941 Views	View on YouTube Download Video

Let's explore drug design and medicinal chemistry by looking at GSK's development of hepatitis C virus inhibitors!

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Correction: Before the nerds call me, some visuals are missing the N-methyl group on the amide and the aryl fluoride on the inhibitor

00:00 Drug discovery is not easy
02:30 What is Hepatitis C and why do we care?
07:14 How to inhibit a virus
08:57 Chemical optimization and structure-activity relationship
13:22 Unexpected turn of events in clinical development
18:44 Implications of the new design for DMPK and clinical success

Key references:
– Design of N-benzoxaborole benzofuran GSK8175 — Optimization of human pharmacokinetics inspired by metabolites of a failed clinical HCV inhibitor: J. Med. Chem. 2019, 62, 7, 3254
– Discovery of a potent boronic acid-derived inhibitor of HCV RNA-dependent RNA polymerase: J. Med. Chem. 2014, 57, 5, 1902
– HCV796: a selective inhibitor of nonstructural protein polymerase 5B with potent anti-hepatitis C virus activity in vitro, in mice with chimeric human livers, and in hepatitis C virus-infected humans: Hepatology 2009, 49, 3, 745

Some recommended books on organic synthesis:
– Clayden, Greeves, Warren; Organic Chemistry (Basic knowledge of organic chemistry)
– Wyatt, Warren; Organic Synthesis: The Disconnection Approach (excellent introduction to retrosynthesis)
– Kurti, Czako; Strategic Applications of Named Reactions in Organic Synthesis (A Complete Toolbox of Functional Group Reactions and Their Applications with Common Conditions)
– Nicolaou et al; Classics in Total Synthesis 1-3 (the ultimate total synthesis trilogy)
– Nicolaou; Molecules That Changed the World (the world's most important molecules and their impact on everyday life)
– Carreira, Kvaerno; Classics in stereoselective synthesis (compilation of revolutionary methods of stereoselective synthesis and application to the synthesis of stereochemically complex structures)