- Discovery of Novel Aminotetralines and Aminochromanes as Selective and Competitive Glycine Transporter 1 (GlyT1) Inhibitors
-
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.
- 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)
-
- Bifunctional Br?nsted Base Catalyst Enables Regio-, Diastereo-, and Enantioselective Cα-Alkylation of β-Tetralones and Related Aromatic-Ring-Fused Cycloalkanones
-
The catalytic asymmetric synthesis of both α-substituted and α,α-disubstituted (quaternary) β-tetralones through direct α-functionalization of the corresponding β-tetralone precursor remains elusive. A designed Br?nsted base-squaramide bifunctional catalyst promotes the conjugate addition of either unsubstituted or α-monosubstituted β-tetralones to nitroalkenes. Under these reaction conditions, not only enolization, and thus functionalization, occurs at the α-carbon atom of the β-tetralone exclusively, but adducts including all-carbon quaternary centers are also formed in highly diastereo- and enantioselective manner.
- Urruzuno, I?aki,Mugica, Odei,Oiarbide, Mikel,Palomo, Claudio
-
supporting information
p. 2059 - 2063
(2017/02/15)
-
- PROCESS FOR PREPARING BICYCLIC AMINE DERIVATIVES
-
The present invention provides a process for preparing a bicyclic amine derivative of the for-mula (Ia) or (Ib), (Formulae (Ia) (Ib)) comprising the rhodium-catalyzed asymmetric hydrogenation of an enamine of the formula (II), (Formula (II)) in the presen
- -
-
Page/Page column 67; 68
(2014/01/18)
-
- N-SUBSTITUTED AMINOBENZOCYCLOHEPTENE, AMINOTETRALINE, AMINOINDANE AND PHENALKYLAMINE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM, AND THEIR USE IN THERAPY
-
The present invention relates to N-substituted aminobenzocycloheptene, aminotetraline, aminoindane and phenalkylamine derivatives of the formula (I), (II), (III) or (IV) or a physiologically tolerated salt thereof.The invention relates to pharmaceutical compositions comprising such N-substituted aminobenzocycloheptene, aminotetraline, aminoindane and phenalkylamine derivatives, and the use of such N-substituted aminobenzocycloheptene, aminotetraline, aminoindane and phenalkylamine derivatives for therapeutic purposes. The N-substituted aminobenzocycloheptene, aminotetraline, aminoindane and phenalkylamine derivatives are GlyT1 inhibitors.
- -
-
Paragraph 0696; 0697; 0698
(2013/06/04)
-
- N-aralkylaminotetralins as ligands for the neuropeptide Y Y5 receptor
-
β-Aminotetralin derivatives of the formula: which are ligands for the neuropeptide Y Y5 (NPY5) receptor, methods of preparation and pharmaceutical compositions containing a β-aminotetralin derivative as the active ingredient are described. The 62 -aminotetralins are useful in the treatment of disorders and diseases associated with NPY receptor subtype Y5.
- -
-
-