Lead optimization toward proof-of-concept tools for Huntington's disease within a 4-(1H-pyrazol-4-yl)pyrimidine class of pan-JNK inhibitors

Journal of Medicinal Chemistry
John WityakCelia Dominguez

Abstract

Through medicinal chemistry lead optimization studies focused on calculated properties and guided by X-ray crystallography and computational modeling, potent pan-JNK inhibitors were identified that showed submicromolar activity in a cellular assay. Using in vitro ADME profiling data, 9t was identified as possessing favorable permeability and a low potential for efflux, but it was rapidly cleared in liver microsomal incubations. In a mouse pharmacokinetics study, compound 9t was brain-penetrant after oral dosing, but exposure was limited by high plasma clearance. Brain exposure at a level expected to support modulation of a pharmacodynamic marker in mouse was achieved when the compound was coadministered with the pan-cytochrome P450 inhibitor 1-aminobenzotriazole.

References

Apr 1, 1994·Fundamental and Applied Toxicology : Official Journal of the Society of Toxicology·C L MeschterL S Kaufman
Apr 2, 1996·Proceedings of the National Academy of Sciences of the United States of America·J HambletonA L DeFranco
Oct 1, 1998·Structure·Z WangE J Goldsmith
Nov 22, 2001·Proceedings of the National Academy of Sciences of the United States of America·B L BennettD W Anderson
Feb 25, 2003·The Journal of Biological Chemistry·Karine MerienneYvon Trottier
May 29, 2003·Current Drug Targets. CNS and Neurological Disorders·Donna Bozyczko-CoyneRobert L Hudkins
Jul 18, 2003·American Journal of Physiology. Cell Physiology·Mònica ComaladaAntonio Celada
Oct 17, 2003·Journal of Medicinal Chemistry·Alejandra TrejoDavid M Goldstein
Mar 19, 2004·Journal of Medicinal Chemistry·Richard A FriesnerPeter S Shenkin
Mar 19, 2004·Journal of Medicinal Chemistry·Thomas A HalgrenJay L Banks
Oct 27, 2004·Drug Discovery Today·Lynn Resnick, Myles Fennell
Sep 6, 2005·Bioorganic & Medicinal Chemistry Letters·Britt-Marie SwahnLiselotte Ohberg
Dec 13, 2005·Bioorganic & Medicinal Chemistry Letters·Britt-Marie SwahnJenny Viklund
Dec 30, 2006·Bioorganic & Medicinal Chemistry Letters·Richard M AngellRuolan Wang
Apr 27, 2007·Bioorganic & Medicinal Chemistry Letters·Mahbub AlamLaura J Tait
Jul 8, 2008·Molecular and Cellular Neurosciences·Barbara L ApostolLeslie Michels Thompson
Aug 5, 2008·Mini Reviews in Medicinal Chemistry·Philip LoGrasso, Theodore Kamenecka
Nov 22, 2008·Experimental Neurology·V PerrinN Déglon
Mar 24, 2009·Bioorganic & Medicinal Chemistry Letters·John A ChristopherJames R Musgrave
Mar 31, 2009·Bioorganic & Medicinal Chemistry Letters·Paul S HumphriesDavid M Wilhite
Feb 12, 2010·Journal of Medicinal Chemistry·M Arshad Siddiqui, Panduranga A Reddy
Dec 28, 2010·Bioorganic & Medicinal Chemistry Letters·Romain NoëlTheodore M Kamenecka
Feb 15, 2011·Bioorganic & Medicinal Chemistry Letters·Simeon BowersIrene Griswold-Prenner
Oct 29, 2011·The Journal of Biological Chemistry·Alessandra SclipTiziana Borsello

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Citations

Jan 5, 2018·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Rowan StringerMarc Bigaud
Jan 1, 2021·Chemical Reviews·Pavel K Mykhailiuk
Oct 30, 2020·Frontiers in Aging Neuroscience·Caroline L Benn, Lee A Dawson
Mar 30, 2021·Computational and Structural Biotechnology Journal·Veronika Temml, Zsofia Kutil

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