3648-86-0Relevant academic research and scientific papers
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.
Visible Light-Mediated Decarboxylation Rearrangement Cascade of Aryl- N-(acyloxy)phthalimides
Faderl, Christian,Budde, Simon,Kachkovskyi, Georgiy,Rackl, Daniel,Reiser, Oliver
, p. 12192 - 12206 (2018/09/21)
A Smiles-type radical rearrangement induced by visible-light-mediated decarboxylation of w-aryl-N-(acyloxy)phthalimides was developed, giving rise to pharmacologically important substance classes: phenylethylamine derivatives, dihydroisoquinolinones, and
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.
High-yield method for the preparation of 1,3,4,5-tetrahydro-7-methoxy-2 H-1-benzazepin-2-one with excellent regio-and stereoselectivity
Piao, Feng-Yu,Xie, Yu-Zhong,Zhang, Wen-Bin,Zhang, Wei,Han, Rong-Bi
, p. 1920 - 1930 (2013/05/22)
We have surveyed the effects of different acid catalysts, reaction times, and temperatures on the yield, regioselectivity, and stereoselectivity and calculated the ketoxime isomerization and activation energy of the title compound. A facile synthetic proc
Aromatic ring functionalization of benzolactam derivatives: New potent dopamine D3 receptor ligands
Ortega, Raquel,Hübner, Harald,Gmeiner, Peter,Masaguer, Christian F.
supporting information; experimental part, p. 2670 - 2674 (2011/06/20)
Since the discovery of the dopamine D3 receptor, an intensive effort has been directed toward the development of potent and selective ligands in order to elucidate the function and potential therapeutic advantages of targeting D3 rec
The application of the schmidt reaction and beckmann rearrangement to the synthesis of bicyclic lactams: Some mechanistic considerations
Crosby, Ian T.,Shin, James K.,Capuano, Ben
experimental part, p. 211 - 226 (2011/06/21)
The syntheses of some methoxy-substituted bicyclic lactams, of the types 3 and 4, are reported employing two different conditions for the Schmidt reaction of appropriate ketones and employing two different conditions for the Beckmann rearrangement of the corresponding ketoximes. The alkyl to aryl migration ratios of the reactions were determined by high-performance liquid chromatography analysis of the reactions. The mechanisms of the reactions reported are discussed, some limitations of the reported mechanisms identified, and an alternative mechanism proposed in light of the outcomes of the various reactions. Application of the Schmidt reaction and Beckmann rearrangement was used for the synthesis of some chloro bicyclic lactams, of the types 3 and 4. CSIRO 2010.
SAR studies of capsazepinoid bronchodilators. Part 1: The importance of the catechol moiety and aspects of the B-ring structure
Dalence-Guzman, Maria F.,Berglund, Magnus,Skogvall, Staffan,Sterner, Olov
, p. 2499 - 2512 (2008/09/21)
Capsazepine as well as its derivatives and analogues are general inhibitors of constriction of human small airways. From a systematic variation of the capsazepine structure, divided into four regions, SARs were established. This part concerns the catechol moiety of the A-ring as well as the 2,3,4,5-tetrahydro-1H-2-azepine moiety (the B-ring) of capsazepine. It is revealed that a conformational constrain (as a fused ring) is important and that compounds with a six-membered B-ring (as a 1,2,3,4-tetrahydroisoquinoline) in general are more potent than the corresponding isoindoline, 2,3,4,5-tetrahydro-1H-2-benzazepine and 2,3,4,5-tetrahydro-1H-3-benzazepine derivatives.
Structure activity relationship studies of carboxamido-biaryl ethers as opioid receptor antagonists (OpRAs). Part 2
Takeuchi, Kumiko,Holloway, William G.,Mitch, Charles H.,Quimby, Steven J.,McKinzie, Jamie H.,Suter, Todd M.,Statnick, Michael A.,Surface, Peggy L.,Emmerson, Paul J.,Thomas, Elizabeth M.,Siegel, Miles G.
, p. 6841 - 6846 (2008/09/17)
A series of 6-bicycloaryloxynicotinamides were identified as opioid receptor antagonists at mu, kappa, and delta receptors. Compounds in the 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide scaffold exhibited potent in vitro functional antagonism at all three receptors.
Synthesis and SAR of novel histamine H3 receptor antagonists
Jesudason, Cynthia D.,Beavers, Lisa S.,Cramer, Jeffrey W.,Dill, Joelle,Finley, Don R.,Lindsley, Craig W.,Stevens, F. Craig,Gadski, Robert A.,Oldham, Samuel W.,Pickard, R. Todd,Siedem, Christopher S.,Sindelar, Dana K.,Singh, Ajay,Watson, Brian M.,Hipskind, Philip A.
, p. 3415 - 3418 (2007/10/03)
The synthesis and biological evaluation of novel tetrahydroisoquinoline, tetrahydroquinoline, and tetrahydroazepine antagonists of the human and rat H3 receptors are described. The substitution around these rings as well as the nature of the substituent on nitrogen is explored. Several compounds with high affinity and selectivity for the human and rat H3 receptors are reported.
