Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020672 (hypothermia)
 17,327 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined the effects of p.o. administered 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1H-1-b enzazepin-8- yl)-1-propanone fumarate (TAK-147), a novel AChE inhibitor, on impaired learning and memory in animal models. At 1 to 3 mg/kg, TAK-147 ameliorated the passive avoidance deficit induced by diazepam. TAK-147 did not affect delayed-matching-to-position (DMTP) performance of normal rats at doses of 1 to 30 mg/kg assessed by using a three-lever operant chamber, but 9-amino-tetrahydroacridine disrupted the DMTP response at 5 to 20 mg/kg. Scopolamine (0.02-0.1 mg/kg s.c.) impaired DMTP performance, whereas methylscopolamine did not affect the DMTP task. TAK-147 ameliorated the impairment of DMTP performance induced by scopolamine without affecting the general behavior of the rats; however, 9-amino-tetrahydroacridine produced no significant amelioration of the impairment. The intraventricular injection of AF64A disrupted differential-reinforcement-of-low-rate 10-sec performance in rats, as demonstrated by marked decreases in reinforcement rate and response efficiency. TAK-147 slightly increased the reinforcement rate in AF64A-treated rats at a low dose of 1 mg/kg, but the effect was not significant statistically. TAK-147 had no significant effect on the duration of immobility in rats in a forced swimming test at doses of 2 to 10 mg/kg. 9-Amino-tetrahydroacridine prolonged the duration of immobility at 5 to 20 mg/kg. Furthermore, TAK-147 reversed reserpine-induced hypothermia and ptosis in mice at doses of 3 to 10 mg/kg, a result that implies an antidepressant-like action. These results indicate that TAK-147 ameliorates learning and memory impairment in animal models without affecting the general behavior or causing behavioral depression and suggest that TAK-147 may be useful for the treatment of Alzheimer's disease.
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PMID:Effects of 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1 -H-1-benzazepin-8-yl)-1-propanone fumarate (TAK-147), a novel acetylcholinesterase inhibitor, on impaired learning and memory in animal models. 866 90

Ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate (TAK-242), a novel small molecule that selectively inhibits Toll-like receptor 4-mediated signaling, inhibits various kinds of inflammatory mediators such as nitric oxide (NO), tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, IL-6, IL-10, macrophage inhibitory protein (MIP)-2 and prostaglandin E2 from lipopolysaccharide (LPS)-stimulated macrophages. The effects of TAK-242 were evaluated in a mouse model of endotoxin shock. Intravenous administration of TAK-242 to mice 1 h before LPS challenge dose-dependently inhibited LPS-induced increases in serum levels of TNF-alpha, IL-1beta, IL-6, IL-10, MIP-2, and NO metabolites. TAK-242 protected mice from LPS-induced lethality in a similar dose-dependent manner, and rescued 100% of mice at a dose of 1 mg/kg. Interestingly, TAK-242 worked quickly, and showed beneficial effects even when administered after LPS challenge. Even though increases in serum levels of IL-6 and hypothermia were already evident 2 h after LPS challenge, TAK-242 administration inhibited further increase in IL-6 levels and decrease in body temperature. LPS-induced increases in serum levels of organ dysfunction markers, such as alanine aminotransferase, total bilirubin, and blood urea nitrogen, were also significantly suppressed by post-treatment as well as pre-treatment. Furthermore, administration of 3 mg/kg TAK-242 significantly increased survival of mice, even when given 4 h after LPS challenge. These results suggest that TAK-242 protects mice against LPS-induced lethality by inhibiting production of multiple cytokines and NO. TAK-242 has a quick onset of action and provides significant benefits by post-treatment, suggesting that it may be a promising drug candidate for the treatment of sepsis.
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PMID:Therapeutic effects of TAK-242, a novel selective Toll-like receptor 4 signal transduction inhibitor, in mouse endotoxin shock model. 1763

Necroptosis, a form of programmed cell death, plays a critical role in various diseases, including inflammatory, infectious, and degenerative diseases. We previously identified N-(7-cyano-6-(4-fluoro-3-(2-(3-(trifluoromethyl)phenyl)acetamido)phenoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamide (TAK-632) (6) as a potent inhibitor of necroptosis by targeting both receptor-interacting protein kinase 1 (RIPK1) and 3 (RIPK3) kinases. Herein, we performed three rounds of structural optimizations of TAK-632 and elucidated structure-activity relationships to generate more potent inhibitors by targeting RIPK3. The analogues with carbamide groups exhibited great antinecroptotic activities, and compound 42 showed >60-fold selectivity for RIPK3 than RIPK1. It blocked necrosome formation by specifically inhibiting the phosphorylation of RIPK3 in necroptotic cells. In a tumor necrosis factor-induced systemic inflammatory response syndrome model, it significantly protected mice from hypothermia and death at a dose of 5 mg/kg, which was much more effective than TAK-632. Moreover, it showed favorable and druglike pharmacokinetic properties in rats with an oral bioavailability of 25.2%. Thus, these RIPK3-targeting small molecules represent promising lead structures for further development.
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PMID:N-(7-Cyano-6-(4-fluoro-3-(2-(3-(trifluoromethyl)phenyl)acetamido)phenoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamide (TAK-632) Analogues as Novel Necroptosis Inhibitors by Targeting Receptor-Interacting Protein Kinase 3 (RIPK3): Synthesis, Structure-Activity Relationships, and in Vivo Efficacy. 3109 85