3648-86-0Relevant articles and documents
1-[2-(1-Cyclobutylpiperidin-4-yloxy)-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl]propan-1-one: a Histamine H3 Receptor Inverse Agonist with Efficacy in Animal Models of Cognition
Shinde, Anil Karbhari,Badange, Rajesh Kumar,Reballi, Veena,Achanta, Pramod Kumar,Bojja, Kumar,Manchineella, Sravanthi,Rao Muddana, Nageswara,Subramanian, Ramkumar,Choudary Palacharla, Raghava,Benade, Vijay,Jayarajan, Pradeep,Thentu, Jagadeesh Babu,Lingavarapu, Bujji Babu,Yarra, Sivasekhar,Kagita, Narendra,Rao Doguparthi, Mallikarjuna,Mohammed, Abdul Rasheed,Nirogi, Ramakrishna
, (2021/11/23)
A series of chemical optimizations, which was guided by in vitro affinity at histamine H3 receptor (H3R), modulation of lipophilicity, ADME properties and preclinical efficacy resulted in the identification of 1-[2-(1-cyclobutylpiperidin-4-yloxy)-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl]propan-1-one (45 e) as a potent and selective (Ki=4.0 nM) H3R inverse agonist. Dipsogenia induced by (R)-α-methylhistamine was dose dependently antagonized by 45 e, confirming its functional antagonism at H3R. It is devoid of hERG and phospholipidosis issues. Compound 45 e has adequate oral exposures and favorable half-life in both rats and dogs. It has demonstrated high receptor occupancy (ED80=0.22 mg/kg) and robust efficacy in object recognition task and, dose dependently increased acetylcholine levels in brain. The sub-therapeutic doses of 45 e in combination with donepezil significantly increased acetylcholine levels. The potent affinity, selectivity, in vivo efficacy and drug like properties together with safety, warrant for further development of this molecule for potential treatment of cognitive disorders associated with Alzheimer's disease.
Optimization of 4-(N-cycloamino)phenylquinazolines as a novel class of tubulin-polymerization inhibitors targeting the colchicine site
Wang, Xiao-Feng,Guan, Fang,Ohkoshi, Emika,Guo, Wanjun,Wang, Lili,Zhu, Dong-Qing,Wang, Sheng-Biao,Wang, Li-Ting,Hamel, Ernest,Yang, Dexuan,Li, Linna,Qian, Keduo,Morris-Natschke, Susan L.,Yuan, Shoujun,Lee, Kuo-Hsiung,Xie, Lan
, p. 1390 - 1402 (2014/03/21)
The 6-methoxy-1,2,3,4-tetrahydroquinoline moiety in prior leads 2-chloro- and 2-methyl-4-(6-methoxy-3,4-dihydroquinolin-1(2H)-yl)quinazoline (1a and 1b) was modified to produce 4-(N-cycloamino)quinazolines (4a-c and 5a-m). The new compounds were evaluated in cytotoxicity and tubulin inhibition assays, resulting in the discovery of new tubulin-polymerization inhibitors. 7-Methoxy-4-(2-methylquinazolin-4-yl)-3,4-dihydroquinoxalin-2(1H)-one (5f), the most potent compound, exhibited high in vitro cytotoxic activity (GI 50 1.9-3.2 nM), significant potency against tubulin assembly (IC 50 0.77 μM), and substantial inhibition of colchicine binding (99% at 5 μM). In mechanism studies, 5f caused cell arrest in G2/M phase, disrupted microtubule formation, and competed mostly at the colchicine site on tubulin. Compound 5f and N-methylated analogue 5g were evaluated in nude mouse MCF7 xenograft models to validate their antitumor activity. Compound 5g displayed significant in vivo activity (tumor inhibitory rate 51%) at a dose of 4 mg/kg without obvious toxicity, whereas 5f unexpectedly resulted in toxicity and death at the same dose.
One-pot synthesis of five-, six-, and seven-membered lactams via Bu 3SnH-mediated reductive cyclization of azido amides
Lee, Su-Jeong,Heo, In-Jung,Cho, Chang-Woo
experimental part, p. 739 - 741 (2012/04/23)
-
