Neurotrophic 3,9-bis[(alkylthio)methyl]-and-bis(alkoxymethyl)-K-252a derivatives

Journal of Medicinal Chemistry
M KanekoC Murakata

Abstract

A series of 3,9 disubstituted [(alkylthio)methyl]- and (alkoxymethyl)-K-252a derivatives was synthesized with the aim of enhancing and separating the neurotrophic properties from the undesirable NGF (trk A kinase) and PKC inhibitory activities of K-252a. Data from this series reveal that substitution in the 3- and 9-positions of K-252a with these groups reduces trk A kinase inhibitory properties approximately 100- to > 500-fold while maintaining or in certain cases enhancing the neurotrophic activity. From this research, 3,9-bis[(ethylthio)methyl]-K-252a (8) was identified as a potent and selective neurotrophic agent in vitro as measured by enhancement of choline acetyltransferase activity in embryonic rat spinal cord and basal forebrain cultures. Compound 8 was found to have weak kinase inhibitory activity for trk A, protein kinase C1 protein kinase A, and myosin light chain kinase. On the basis of the in vitro profile, 8 was evaluated in in vivo models suggestive of neurological diseases. Compound 8 was active in preventing degeneration of cholinergic neurons of the nucleus basalis magnocellularis (NBM) and reduced developmentally programmed cell death (PCD) of female rat spinal nucleus of the bulbocavernosus motoneurons and ...Continue Reading

References

Jul 1, 1989·Trends in Neurosciences·R W Oppenheim
Jan 30, 1987·Biochemical and Biophysical Research Communications·H KaseM Kaneko
Oct 1, 1980·Physiological Reviews·H Thoenen, Y A Barde
Jun 1, 1994·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·A R Saltiel, S J Decker
Nov 1, 1993·Experimental Neurology·M E LewisJ L Vaught
Apr 5, 1996·Analytical Biochemistry·T S AngelesC A Dionne

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Citations

Mar 17, 2004·Biochimica Et Biophysica Acta·Marie A BogoyevitchRenae K Barr
Feb 26, 2000·Trends in Pharmacological Sciences·H U Saragovi, K Gehring
Jan 5, 2002·Bioorganic & Medicinal Chemistry Letters·Chikara MurakataRobert L Hudkins
Sep 25, 2002·Bioorganic & Medicinal Chemistry Letters·Diane E Gingrich, Robert L Hudkins
Jan 10, 2009·The Journal of Antibiotics·Hirofumi Nakano, Satoshi Omura
Aug 3, 2002·Respirology : Official Journal of the Asian Pacific Society of Respirology·Sachiko FuruichiTakashi Horie
Mar 15, 2008·Respirology : Official Journal of the Asian Pacific Society of Respirology·Shinichi HayashiShu Hashimoto
Apr 19, 2007·Acta Pharmacologica Sinica·Jie CuiZhi-Heng Xu
Jan 28, 2004·Annual Review of Pharmacology and Toxicology·Leo H WangEugene M Johnson
Jun 14, 2013·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Daniel F MarkerHarris A Gelbard
Nov 22, 2001·Proceedings of the National Academy of Sciences of the United States of America·B L BennettD W Anderson
Apr 14, 2000·Brain Pathology·G S RobertsonJ B Schulz
Jun 6, 2013·Journal of Neurovirology·Qing MaGiovanni Schifitto
Jun 19, 2015·Expert Opinion on Drug Discovery·Yuan Lin, Yi Zheng
Nov 1, 2005·Expert Opinion on Investigational Drugs·Guang-Yi Zhang, Quan-Guang Zhang
Feb 22, 2012·Neurotoxicology·Anumantha KanthasamyArthi Kanthasamy
Dec 31, 2011·Neurotoxicology·Dominik PöltlMarcel Leist
Jul 8, 2008·Molecular and Cellular Neurosciences·Barbara L ApostolLeslie Michels Thompson
Mar 8, 2005·Journal of Neurochemistry·Søren LundMarcel Leist
Sep 6, 2003·Clinical and Experimental Allergy : Journal of the British Society for Allergy and Clinical Immunology·K MizumuraT Horie
Aug 16, 2005·Progress in Neurobiology·Clive R Bramham, Elhoucine Messaoudi
Feb 28, 2014·British Journal of Pharmacology·Maté BiroWolfgang Weninger
Nov 20, 2012·Cellular Logistics·Natalia Coleman, Joseph Kissil
Nov 26, 1998·Molecular and Cellular Neurosciences·S D Skaper, F S Walsh
Jun 29, 2016·Journal of Neuroimmune Pharmacology : the Official Journal of the Society on NeuroImmune Pharmacology·Weizhe LiYuanan Lu
Apr 25, 2018·Biomedical Engineering Online·Chong NingShi-Ying Huang
Feb 4, 2005·Angewandte Chemie·Zhaoyang Meng, Samuel J Danishefsky
Feb 19, 2005·Movement Disorders : Official Journal of the Movement Disorder Society·Robert M SilvaRobert E Burke
Jun 2, 2007·ChemMedChem·Simona Margutti, Stefan A Laufer
Sep 5, 2002·Nature Reviews. Molecular Cell Biology·Kathleen A Gallo, Gary L Johnson

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