Neurotrophic 3,9-bis[(alkylthio)methyl]-and-bis(alkoxymethyl)-K-252a derivatives.
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 embryonic chick lumbar motoneurons.
Kaneko
M
M
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
Saito
Y
Y
Saito
H
H
Matsumoto
T
T
Matsuda
Y
Y
Vaught
J L
JL
Dionne
C A
CA
Angeles
T S
TS
Glicksman
M A
MA
Neff
N T
NT
Rotella
D P
DP
Kauer
J C
JC
Mallamo
J P
JP
Hudkins
R L
RL
Murakata
C
C
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002227:Carbazoles / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*; D002642:Chick Embryo; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D026121:Indole Alkaloids; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology; D009410:Nerve Degeneration / Q000187:drug effects; D009414:Nerve Growth Factors / Q000037:antagonists & inhibitors; D009474:Neurons / Q000187:drug effects* / Q000502:physiology*; D016548:Prosencephalon / Q000196:embryology / Q000201:enzymology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA; D017475:Receptors, Nerve Growth Factor; D013116:Spinal Cord / Q000196:embryology / Q000201:enzymology; D013377:Substantia Innominata / Q000166:cytology
D002227:Carbazoles; D004791:Enzyme Inhibitors; D026121:Indole Alkaloids; D007211:Indoles; D009414:Nerve Growth Factors; D011518:Proto-Oncogene Proteins; D017475:Receptors, Nerve Growth Factor; C106592:3,9-bis((ethylthio)methyl)-K-252a; C049985:staurosporine aglycone; D002795:Choline O-Acetyltransferase; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA; D011493:Protein Kinase C