Fragment-Based Discovery of Pyrimido[1,2-b]indazole PDE10A Inhibitors

Chemical & Pharmaceutical Bulletin
Ayaka ChinoNaoyuki Masuda

Abstract

In this study, we report the identification of potent pyrimidoindazoles as phosphodiesterase10A (PDE10A) inhibitors by using the method of fragment-based drug discovery (FBDD). The pyrazolopyridine derivative 2 was found to be a fragment hit compound which could occupy a part of the binding site of PDE10A enzyme by using the method of the X-ray co-crystal structure analysis. On the basis of the crystal structure of compound 2 and PDE10A protein, a number of compounds were synthesized and evaluated, by means of structure-activity relationship (SAR) studies, which culminated in the discovery of a novel pyrimidoindazole derivative 13 having good physicochemical properties.

References

Jun 9, 1999·Proceedings of the National Academy of Sciences of the United States of America·S H SoderlingJ A Beavo
Feb 15, 2001·Journal of Medicinal Chemistry·M RowleyP H Hutson
Sep 22, 2001·Acta Crystallographica. Section D, Biological Crystallography·J Navaza
May 1, 1997·Acta Crystallographica. Section D, Biological Crystallography·G N MurshudovE J Dodson
Dec 2, 2004·Acta Crystallographica. Section D, Biological Crystallography·Paul Emsley, Kevin Cowtan
Apr 6, 2005·Drug Discovery Today·Cele Abad-Zapatero, James T Metz
Jul 19, 2005·Drug Discovery Today·Robin A E CarrDavid C Rees
Mar 29, 2007·Proceedings of the National Academy of Sciences of the United States of America·Huanchen WangHengming Ke
Feb 22, 2008·The Journal of Pharmacology and Experimental Therapeutics·C J SchmidtF S Menniti
Mar 31, 2009·Schizophrenia Research·Rajiv TandonMatcheri S Keshavan
Aug 8, 2009·The Journal of Pharmacology and Experimental Therapeutics·Steven M GrauerNicholas J Brandon
Aug 28, 2013·Bioorganic & Medicinal Chemistry·John Paul KilburnJacob Nielsen
Feb 5, 2014·Journal of Chemical Information and Modeling·Diane Joseph-McCarthyDemetri Moustakas
Apr 15, 2014·Bioorganic & Medicinal Chemistry Letters·Sanjib DasAbraham Thomas
May 20, 2014·Bioorganic & Medicinal Chemistry·Ayaka ChinoMasaki Tomishima
Dec 17, 2014·Journal of Medicinal Chemistry·José Manuel Bartolomé-NebredaSusana Conde-Ceide
Apr 13, 2015·Bioorganic & Medicinal Chemistry Letters·Douglas F BurdiMichael C Hewitt
Oct 7, 2015·Frontiers in Neurology·Michael J WaskoChristopher K Surratt
Oct 24, 2015·Bioorganic & Medicinal Chemistry·Masato YoshikawaTakahiko Taniguchi
Nov 26, 2015·Bioorganic & Medicinal Chemistry Letters·Izzat T RaheemChristopher D Cox
Dec 18, 2015·The Journal of Pharmacology and Experimental Therapeutics·Eri ShiraishiHaruhide Kimura
Jan 1, 1997·Methods in Enzymology·Zbyszek Otwinowski, Wladek Minor

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Citations

Jan 28, 2020·Biochemical Society Transactions·James OsborneHarren Jhoti
Dec 16, 2018·Molecular Diversity·Ahmad ShaabaniRonak Afshari
Jan 9, 2020·Journal of Medicinal Chemistry·Daniel A ErlansonPaul N Mortenson

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