155014-05-4Relevant articles and documents
INHIBITORS OF JUN N-TERMINAL KINASE
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Page/Page column 146, (2010/08/18)
The present disclosure provides inhibitors of c-Jun N-terminal kinases (JNK) having a structure according to the following formula (I): or a salt or solvate thereof, wherein ring A, Ca, Cb, Z, R5, W and Cy are defined herein. The disclosure further provides pharmaceutical compositions including the compounds of the present disclosure and methods of making and using the compounds and compositions of the present disclosure, e.g., in the treatment and prevention of various disorders, such as Alzheimer's disease.
The synthesis and biological evaluation of quinolyl-piperazinyl piperidines as potent serotonin 5-HT1A antagonists
Childers, Wayne E.,Havran, Lisa M.,Asselin, Magda,Bicksler, James J.,Chong, Dan C.,Grosu, George T.,Shen, Zhongqi,Abou-Gharbia, Magid A.,Bach, Alvin C.,Harrison, Boyd L.,Kagan, Natasha,Kleintop, Teresa,Magolda, Ronald,Marathias, Vasilios,Robichaud, Albert J.,Sabb, Annmarie L.,Zhang, Mei-Yi,Andree, Terrance H.,Aschmies, Susan H.,Beyer, Chad,Comery, Thomas A.,Day, Mark,Grauer, Steven M.,Hughes, Zoe A.,Rosenzweig-Lipson, Sharon,Platt, Brian,Pulicicchio, Claudine,Smith, Deborah E.,Sukoff-Rizzo, Stacy J.,Sullivan, Kelly M.,Adedoyin, Adedayo,Huselton, Christine,Hirst, Warren D.
experimental part, p. 4066 - 4084 (2010/08/06)
As part of an effort to identify 5-HT1A antagonists that did not possess typical arylalkylamine or keto/amido-alkyl aryl piperazine scaffolds, prototype compound 10a was identified from earlier work in a combined 5-HT 1A antagonist/SSRI program. This quinolyl-piperazinyl piperidine analogue displayed potent, selective 5-HT1A antagonism but suffered from poor oxidative metabolic stability, resulting in low exposure following oral administration. SAR studies, driven primarily by in vitro liver microsomal stability assessment, identified compound 10b, which displayed improved oral bioavailability and lower intrinsic clearance. Further changes to the scaffold (e.g., 10r) resulted in a loss in potency. Compound 10b displayed cognitive enhancing effects in a number of animal models of learning and memory, enhanced the antidepressant-like effects of the SSRI fluoxetine, and reversed the sexual dysfunction induced by chronic fluoxetine treatment.
Dual stimulatory and inhibitory effects of fluorine-substitution on mutagenicity: An extension of the enamine epoxide theory for activation of the quinoline nucleus
Saeki, Ken-Ichi,Kawai, Hiroshi,Kawazoe, Yutaka,Hakura, Atsushi
, p. 646 - 650 (2007/10/03)
Nineteen mono- and di-fluorinated derivatives of quinoline, 1,7- phenanthroline, 1,10-phenanthroline, benzo-[h]quinoline, and benzo[f]quinoline were subjected to analysis of their structure-mutagenicity relationships. For this purpose, six new fluorinated derivatives were synthesized. The results support that the enamine epoxide structure of the pyridine moiety, as well as the bay-region epoxide structure, is responsible for mutagenicity. Formation of K-region epoxides might involve a detoxification process rather than mutagenic activation.
