116004-86-5Relevant academic research and scientific papers
Exception That Proves the Rule: Investigation of Privileged Stereochemistry in Designing Dopamine D3R Bitopic Agonists
Battiti, Francisco O.,Newman, Amy Hauck,Bonifazi, Alessandro
, p. 1956 - 1964 (2020)
In this study, starting from our selective D3R agonist FOB02-04A (5), we investigated the chemical space around the linker portion of the molecule via insertion of a hydroxyl substituent and ring-expansion of the trans-cyclopropyl moiety into a trans-cyclohexyl scaffold. Moreover, to further elucidate the importance of the primary pharmacophore stereochemistry in the design of bitopic ligands, we investigated the chiral requirements of (+)-PD128907 ((+)-(4aR,10bR)-2)) by synthesizing and resolving bitopic analogues in all the cis and trans combinations of its 9-methoxy-3,4,4a,10b-tetrahydro-2H,5H-chromeno[4,3-b][1,4] oxazine scaffold. Despite the lack of success in obtaining new analogues with improved biological profiles, in comparison to our current leads, a "negative"result due to a poor or simply not improved biological profile is fundamental toward better understanding chemical space and optimal stereochemistry for target recognition. Herein, we identified essential structural information to understand the differences between orthosteric and bitopic ligand-receptor binding interactions, discriminate D3R active and inactive states, and assist multitarget receptor recognition. Exploring stereochemical complexity and developing extended D3R SAR from this new library complements previously described SAR and inspires future structural and computational biology investigation. Moreover, the expansion of chemical space characterization for D3R agonism may be utilized in machine learning and artificial intelligence (AI)-based drug design, in the future.
D3 RECEPTOR AGONIST COMPOUNDS; METHODS OF PREPARATION; INTERMEDIATES THEREOF; AND METHODS OF USE THEREOF
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Paragraph 0177, (2020/10/21)
Disclosed herein are novel compounds including dopamine D3 receptor agonists, compositions thereof, methods of use thereof, and processes of synthesizing the same. Further disclosed are D3R selective agonist compounds, specifically bitopic ligands comprising chirality.
Discovery of Novel Aminotetralines and Aminochromanes as Selective and Competitive Glycine Transporter 1 (GlyT1) Inhibitors
Amberg, Willi,Lange, Udo E. W.,Ochse, Michael,Pohlki, Frauke,Behl, Berthold,Relo, Ana Lucia,Hornberger, Wilfried,Hoft, Carolin,Mezler, Mario,Sydor, Jens,Wang, Ying,Zhao, Hongyu,Brewer, Jason T.,Dietrich, Justin,Li, Huanqiu,Akritopoulou-Zanze, Irini,Lao, Yanbin,Hannick, Steven M.,Ku, Yi-Yin,Vasudevan, Anil
, p. 7503 - 7524 (2018/09/06)
The glycine transporter 1 (GlyT1) has emerged as a key novel target for the treatment of schizophrenia. Herein, we report the synthesis and biological evaluation of aminotetralines and aminochromanes as novel classes of competitive GlyT1 inhibitors. Starting from a high-throughput screening hit, structure-activity relationship studies led first to the discovery of aminotetralines displaying high GlyT1 potency and selectivity, with favorable pharmacokinetic properties. Systematic investigations of various parameters (e.g., topological polar surface area, number of hydrogen bond donors) guided by ex vivo target occupancy evaluation resulted in lead compounds possessing favorable brain penetration properties as for (7S,8R)-27a. Further optimization revealed compounds with reduced efflux liabilities as for aminochromane 51b. In an in vivo efficacy model (7S,8R)-27a, dose-dependently reversed L-687,414 induced hyperlocomotion in mice with an ED50 of 0.8 mg/kg. All these results suggest (7S,8R)-27a and 51b as new GlyT1 inhibitors worthy of further profiling.
Aminochromane, aminothiochromane and amino-1,2,3,4-tetrahydroquinoline derivatives, pharmaceutical compositions containing them, and their use in therapy
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Paragraph 0490; 0491; 0492, (2015/04/28)
The present invention relates to aminochromane, aminothiochromane and amino-1,2,3,4-tetrahydroquinoline derivatives of the formula (I) or a physiologically tolerated salt thereof The invention relates to pharmaceutical compositions comprising such aminoch
AMINOCHROMANE, AMINOTHIOCHROMANE AND AMINO-1,2,3,4-TETRAHYDROQUINOLINE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM, AND THEIR USE IN THERAPY
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Page/Page column 153; 154, (2013/03/26)
The present invention relates to aminochromane, aminothiochromane and 1,2,3,4-tetrahydroquinoline derivatives of the formula (I), or a physiologically tolerated salt thereof. The invention relates to pharmaceutical compositions comprising such aminochromane, aminothiochromane and amino-1,2,3,4-tetrahydroquinoline derivatives, and the use of such aminochromane, aminothiochromane and amino-1,2,3,4-tetrahydroquinoline derivatives for therapeutic purposes. The aminochromane, aminothiochromane and amino-1,2,3,4-tetrahydroquinoline derivatives are GlyT1 inhibitors
