896085-01-1Relevant academic research and scientific papers
Development of a highly potent, novel M5positive allosteric modulator (PAM) demonstrating CNS exposure: 1-((1H-indazol-5-yl)sulfoneyl)-N-ethyl-N-(2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (ML380)
Gentry, Patrick R.,Kokubo, Masaya,Bridges, Thomas M.,Noetzel, Meredith J.,Cho, Hyekyung P.,Lamsal, Atin,Smith, Emery,Chase, Peter,Hodder, Peter S.,Niswender, Colleen M.,Daniels, J. Scott,Conn, P. Jeffrey,Lindsley, Craig W.,Wood, Michael R.
, p. 7804 - 7810 (2014/12/12)
A functional high throughput screen identified a novel chemotype for the positive allosteric modulation (PAM) of the muscarinic acetylcholine receptor (mAChR) subtype 5 (M5). Application of rapid analog, iterative parallel synthesis efficiently optimized M5potency to arrive at the most potent M5PAMs prepared to date and provided tool compound 8n (ML380) demonstrating modest CNS penetration (human M5EC50= 190 nM, rat M5EC50= 610 nM, brain to plasma ratio (Kp) of 0.36).
Design, synthesis, and biological evaluation of novel piperidine-4- carboxamide derivatives as potent CCR5 inhibitors
Hu, Suwen,Gu, Quan,Wang, Zhilong,Weng, Zhiyong,Cai, Yunrui,Dong, Xiaowu,Hu, Yongzhou,Liu, Tao,Xie, Xin
, p. 259 - 266 (2014/01/06)
Based on a putative 'Y shape' pharmacophore model of CCR5 inhibitors, a series of novel piperidine-4-carboxamide derivatives were designed and synthesized using a group-reverse strategy. Among synthesized target compounds, 16g (IC50 = 25.73 nM) and 16i (IC50 = 25.53 nM) showed equivalent inhibitory activity against CCR5 to that of the positive control maraviroc (IC50 = 25.43 nM) in calcium mobilization assay. Selected compounds were further tested for their antiviral activity in HIV-1 single cycle assay. Two compounds, 16g and 16i, displayed antiviral activity with IC 50 values of 73.01 nM and 94.10 nM, respectively. Additionally, the pharmacokinetic properties and inhibitory potency against hERG of 16g were evaluated, providing a foundation for ongoing optimization.
Design, synthesis, and biological activity of novel 1,4-disubstituted piperidine/piperazine derivatives as CCR5 antagonist-based HIV-1 entry inhibitors
Dong, Ming-Xin,Lu, Lu,Li, Haitao,Wang, Xiaohua,Lu, Hong,Jiang, Shibo,Dai, Qiu-Yun
scheme or table, p. 3284 - 3286 (2012/06/18)
A series of novel 1,4-disubstituted piperidine/piperazine derivatives were designed, synthesized and evaluated for their in vitro activities against HIV-1 Bal (R5) infection in CEMX174 5.25M7 cells. A majority of these compounds showed potent anti-HIV-1 activities with IC50 at nanomolar levels. N-(4-Fluoro-benzyl)piperazine analog B07 hydrochloride exhibited potency against HIV-1 activity similar to that of TAK-220 hydrochloride, but it had much better water solubility (25 mg/ml in phosphate sodium buffer at 25 °C) and oral bioavailability (56%) than TAK-220 hydrochloride (a solubility of 2 mg/ml and oral bioavailability of 1.4%). These results suggest that B07 hydrochloride may serve as a better lead for the development of new anti-HIV-1 therapies or microbicides for treatment and prevent of HIV-1 infection.
