101997-42-6Relevant articles and documents
Design, synthesis and evaluation of cinnamic acid hybrids as multi-target-directed agents for the treatment of Alzheimer's disease
Wang, Keren,Shi, Jian,Zhou, Yi,He, Ying,Mi, Jing,Yang, Jing,Liu, Shuang,Tang, Xiangcheng,Liu, Wenmin,Tan, Zhenghuai,Sang, Zhipei
, (2021/05/03)
Herein, combining 1,2,3,4-tetrahydroisoquinoline and benzylpiperidine groups into cinnamic acid derivatives, a series of novel cinnamic acid hybrids was rationally designed, synthesized and evaluated by the multi-target-directed ligands (MTDLs) strategy.
CCR5 antagonists as anti-HIV-1 agents. Part 3: Synthesis and biological evaluation of piperidine-4-carboxamide derivatives
Imamura, Shinichi,Nishikawa, Youichi,Ichikawa, Takashi,Hattori, Taeko,Matsushita, Yoshihiro,Hashiguchi, Shohei,Kanzaki, Naoyuki,Iizawa, Yuji,Baba, Masanori,Sugihara, Yoshihiro
, p. 397 - 416 (2007/10/03)
Replacement of the 5-oxopyrrolidin-3-yl fragment in the previously reported lead structure with a 1-acetylpiperidin-4-yl group led to the discovery of a novel series of potent CCR5 antagonists. Introduction of small hydrophobic substituents on the central phenyl ring increased the binding affinity, providing low to sub-nanomolar CCR5 antagonists. The selected compound 11f showed excellent antiviral activity against CCR5-using HIV-1 replication in human peripheral blood mononuclear cells (EC50 = 0.59 nM) and an acceptable pharmacokinetic profile in dogs.
CCR5 antagonists as anti-HIV-1 agents. Part 2: Synthesis and biological evaluation of N-[3-(4-benzylpiperidin-1-yl)propyl]-N,N′- diphenylureas
Imamura, Shinichi,Kurasawa, Osamu,Nara, Yoshi,Ichikawa, Takashi,Nishikawa, Youichi,Iida, Takehiro,Hashiguchi, Shohei,Kanzaki, Naoyuki,Iizawa, Yuji,Baba, Masanori,Sugihara, Yoshihiro
, p. 2295 - 2306 (2007/10/03)
We have previously reported the novel lead compound 1a as a CCR5 antagonist for treatment of HIV-1 infection. SAR studies on incorporating various acyl groups as a replacement for the 5-oxopyrrolidine-3-carbonyl group of the lead structure resulted in the
Secondary amides of (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid as inhibitors of pyruvate dehydrogenase kinase
Aicher, Thomas D.,Anderson, Robert C.,Gao, Jiaping,Shetty, Suraj S.,Coppola, Gary M.,Stanton, James L.,Knorr, Douglas C.,Sperbeck, Donald M.,Brand, Leonard J.,Vinluan, Christine C.,Kaplan, Emma L.,Dragland, Carol J.,Tomaselli, Hollis C.,Islam, Amin,Lozito, Robert J.,Liu, Xilin,Maniara, Wieslawa M.,Fillers, William S.,Dominick Delgrande,Walter, Eric,Mann, William R.
, p. 236 - 249 (2007/10/03)
N'-Methyl-N-(4-tert-butyl-1,2,5,6-tetrahydropyridine)thiourea, SDZ048- 619 (1), is a modest inhibitor (IC50 = 180 μM) of pyruvate dehydrogenase kinase (PDHK). In an optimization of the N-methylcarbothioamide moiety of 1, it was discovered that amides with a small acyl group, in particular appropriately substituted amides of (R)-3,3,3-trifluoro-2-hydroxy-2- methylpropionic acid, are inhibitors of PDHK. Utilizing this acyl moiety, herein is reported the rationale leading to the optimization of a series of acylated piperazine derivatives. Methyl substitution of the piperazine at the 2- and 5-positions (with S and R absolute stereochemistry) markedly increased the potency of the lead compound (> 1000-fold). Oral bioavailability of the compounds in this series is good and is optimal (as measured by AUC) when the 4-position of the piperazine is substituted with an electron-poor benzoyl moiety. (+)-1-N-[2,5-(S,R)-Dimethyl-4-N-(4-cyanobenzoyl)piperazine]-(R)- 3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (14e) inhibits PDHK in the primary enzymatic assay with an IC50 of 16 ± 2 nM, enhances the oxidation of [14C]lactate into 14CO2 in human fibroblasts with an EC50 of 57 ± 13 nM, diminishes lactate significantly 2.5 h post-oral-dose at doses as low as 1 μmol/kg, and increases the ex vivo activity of PDH in muscle, liver, and fat tissues in normal Sprague-Dawley rats. These PDHK inhibitors, however, do not lower glucose in diabetic animal models.
