50351-80-9Relevant academic research and scientific papers
Design, synthesis and biological evaluation of brain penetrant benzazepine-based histone deacetylase 6 inhibitors for alleviating stroke-induced brain infarction
Guo, Zheng,Zhang, Zixue,Zhang, Yi,Wang, Guan,Huang, Ziyi,Zhang, Qinwei,Li, Jianqi
, (2021/04/02)
Histone deacetylase 6 (HDAC6) has become a promising therapeutic target for central nervous system diseases due to its more complex protein structure and biological functions. However, low brain penetration of reported HDAC6 inhibitors limits its clinical application in neurological disorders. Therefore, the benzazepine, a brain-penetrant rigid fragment, was utilized to design a series of selective HDAC6 inhibitors to improve brain bioavailability. Various synthetic strategies were applied to assemble the tetrahydro-benzazepine ring, and 22 compounds were synthesized. Among them, compound 5 showed low nanomolar potency and strong isozyme selectivity for the inhibition of HDAC6 (IC50 = 1.8 nM, 141-fold selectivity over HDAC1) with efficient binding patterns like coordination with the zinc ion and π-π stacking effect. Western blot results showed it could efficiently transport into SH-SY5Y cells and selectively enhance the acetylation level of α-tubulin with a moderate effect on Histone H3. Notably, pharmacokinetic studies demonstrated that compound 5 (brain/plasma ratio of 2.30) had an excellent ability to penetrate the blood-brain barrier of C57 mice. In male rats with transient middle cerebral artery occlusion (MCAO), compound 5 significantly reduced the cerebral infarction from 21.22% to 11.47% and alleviated neurobehavioral deficits in post-ischemic treatment, which provided a strong rationale for pursuing HDAC6-based therapies for ischemic stroke.
TETRAHYDRO-BENZOAZEPINE GLYCOSIDASE INHIBITORS
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, (2020/03/15)
Compounds of formula (I') wherein A, R1, R2, T1, T2, T3, T4, L, W, Z, R''', m and n have the meaning according to the claims can be employed, inter alia, for the treatment of tauopathies and Alzheimer's disease.
Tetrahydro-3-benzazepines with fluorinated side chains as NMDA and σ1 receptor antagonists: Synthesis, receptor affinity, selectivity and antiallodynic activity
Thum, Simone,Schepmann, Dirk,Ayet, Eva,Pujol, Marta,Nieto, Francisco R.,Ametamey, Simon M.,Wünsch, Bernhard
, p. 47 - 62 (2019/05/27)
The class of tetrahydro-1H-3-benzazepines was systematically modified in 1-, 3- and 7-position. In particular, a F-atom was introduced in β- or γ-position of the 4-phenylbutyl side chain in 3-position. Ligands with the F-atom in γ-position possess higher
A new facile synthetic route to [11C]GSK189254, a selective PET radioligand for imaging of CNS histamine H3 receptor
Wang, Min,Gao, Mingzhang,Steele, Brandon L.,Glick-Wilson, Barbara E.,Brown-Proctor, Clive,Shekhar, Anantha,Hutchins, Gary D.,Zheng, Qi-Huang
, p. 4713 - 4718 (2012/08/13)
GSK189254 and its corresponding precursor GSK185071B were synthesized from 3-methoxyphenylacetic acid with 6-chloropyridine-3-carbolic acid or 6-chloronicotinamide in 8 and 7 steps with either 6% or 7% and either 14% or 16% yield, respectively. [11/
Synthesis and biological evaluation of N-alkylated 8-oxybenz[c]azepine derivatives as selective PPARδ agonists
Luckhurst, Christopher A.,Ratcliffe, Marianne,Stein, Linda,Furber, Mark,Botterell, Sara,Laughton, David,Tomlinson, Wendy,Weaver, Richard,Chohan, Kamaldeep,Walding, Andrew
scheme or table, p. 531 - 536 (2011/02/27)
We describe the discovery of small molecule benzazepine derivatives as agonists of human peroxisome proliferator-activated receptor δ (PPARδ) that displayed excellent selectivity over the PPARα and PPARγ subtypes. Compound 8 displayed good PK in the rat a
Design, synthesis, and evaluation of fused heterocyclic analogs of SCH 58261 as adenosine A2A receptor antagonists
Shah, Unmesh,Lankin, Claire M.,Boyle, Craig D.,Chackalamannil, Samuel,Greenlee, William J.,Neustadt, Bernard R.,Cohen-Williams, Mary E.,Higgins, Guy A.,Ng, Kwokei,Varty, Geoffrey B.,Zhang, Hongtao,Lachowicz, Jean E.
scheme or table, p. 4204 - 4209 (2009/04/10)
SCH 58261 is a reported adenosine A2A receptor antagonist which is active in rat in vivo models of Parkinson's Disease upon ip administration. However, it has poor selectivity versus the A1 receptor and does not demonstrate oral activity. Quinoline analogs have improved upon the selectivity and pharmacokinetics of SCH 58261, but were difficult to handle due to poor aqueous solubility. We report the design and synthesis of fused heterocyclic analogs of SCH 58261 with aqueous solubility as well as improved A2A receptor binding selectivity and pharmacokinetic properties. In particular, the tetrahydronaphthyridine 4s has excellent A2A receptor in vitro binding affinity and selectivity, is active orally in a rat in vivo model of Parkinson's Disease, and has aqueous solubility of 100 μM at physiological pH.
FUSED BICYCLIC DERIVATIVES OF 2,4-DIAMINOPYRIMIDINE AS ALK AND C-MET INHIBITORS
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Page/Page column 421, (2008/12/05)
The present invention provides a compound of formula I or II or a pharmaceutically acceptable salt form thereof, wherein R1, R2, R3, R4, R5, A1, A2, A3, A4, and A5, are as defined herein. The compounds of formula I or II have ALK and/or c-Met inhibitory activity, and may be used to treat proliferative disorders.
PIPERAZINYL OXOALKYL TETRAHYDROISOQUINOLINES AND RELATED ANALOGUES
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, (2008/06/13)
Piperazinyl oxoalkyl tetrahydroisoquinolines and related analogues of the Formula: are provided, in which variables are as described herein. Such compounds may be used to modulate ligand binding to histamine H3 receptors in vivo or in vitro, and are parti
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.
BENZOAZEPIN-OXY-ACETIC ACID DERIVATIVES AS PPAR-DELTA AGONISTS USED FOR THE INCREASE OF HDL-C, LOWER LDL-C AND LOWER CHOLESTEROL
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Page/Page column 30-31, (2008/06/13)
The invention is directed to compounds of Formula (I) useful as PPAR agonists. Pharmaceutical compositions and methods of treating one or more conditions including, but not limited to, diabetes, nephropathy, neuropathy, retinopathy, polycystic ovary syndr
