- FUSED THIOPHENE AND THIAZOLE DERIVATIVES AS ROR GAMMA MODULATORS
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The present invention provides fused thiophene and thiazole derivatives of formula (I), which may be therapeutically useful, more particularly as RORγ modulators; in which R1, R2, R3, R4, R5, R6, R7, X1, X2, L, m, n and ring A have the meanings given in the specification, and pharmaceutically acceptable salts thereof that are useful in the treatment and prevention of diseases or disorders, in particular their use in disease(s) or disorder(s) where there is an advantage in modulating RORγ receptor. The present invention also provides preparation of the compounds and pharmaceutical formulations comprising at least one of the fused thiophene and thiazole derivatives of formula (I), together with a pharmaceutically acceptable carrier, diluent or excipient therefor.
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Page/Page column 66; 67
(2015/07/16)
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- Dihydrothiazolopyridone derivatives as a novel family of positive allosteric modulators of the metabotropic glutamate 5 (mGlu5) receptor
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Starting from a singleton chromanone high throughput screening (HTS) hit, we describe a focused medicinal chemistry optimization effort leading to the identification of a novel series of phenoxymethyl-dihydrothiazolopyridone derivatives as selective positive allosteric modulators (PAMs) of the metabotropic glutamate 5 (mGlu5) receptor. These dihydrothiazolopyridones potentiate receptor responses in recombinant systems. In vitro and in vivo drug metabolism and pharmacokinetic (DMPK) evaluation allowed us to select compound 16a for its assessment in a preclinical animal screen of possible antipsychotic activity. 16a was able to reverse amphetamine-induced hyperlocomotion in rats in a dose-dependent manner without showing any significant motor impairment or overt neurological side effects at comparable doses. Evolution of our medicinal chemistry program, structure activity, and properties relationships (SAR and SPR) analysis as well as a detailed profile for optimized mGlu5 receptor PAM 16a are described.
- Bartolomé-Nebreda, José Manuel,Conde-Ceide, Susana,Delgado, Francisca,Iturrino, Laura,Pastor, Joaquín,Pena, Miguel ángel,Trabanco, Andrés A.,Tresadern, Gary,Wassvik, Carola M.,Stauffer, Shaun R.,Jadhav, Satyawan,Gogi, Kiran,Vinson, Paige N.,Noetzel, Meredith J.,Days, Emily,Weaver, C. David,Lindsley, Craig W.,Niswender, Colleen M.,Jones, Carrie K.,Conn, P. Jeffrey,Rombouts, Frederik,Lavreysen, Hilde,Macdonald, Gregor J.,Mackie, Claire,Steckler, Thomas
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p. 7243 - 7259
(2013/10/21)
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- Fused thiazolyl alkynes as potent mGlu5 receptor positive allosteric modulators
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A new series of potent fused thiazole mGlu5 receptor positive allosteric modulators (PAMs) (10, 11 and 27-31) are disclosed and details of the SAR and optimization are described. Optimization of alkynyl thiazole 9 (Lu AF11205) led to the identification of potent fused thiazole analogs 10b, 27a, 28j and 31d. In general, substituted cycloalkyl, aryl and heteroaryl carboxamides, and carbamate analogs are mGlu5 PAMs, whereas smaller alkyl carboxamide, sulfonamide and sulfamide analogs tend to be mGlu5 negative allosteric modulators (NAMs).
- Packiarajan, Mathivanan,Grenon, Michel,Zorn, Samuel,Hopper, Allen T.,White, Andrew D.,Chandrasena, Gamini,Pu, Xiaosui,Brodbeck, Robbin M.,Robichaud, Albert J.
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p. 4037 - 4043
(2013/07/25)
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- BICYCLIC THIAZOLES AS ALLOSTERIC MODULATORS OF MGLUR5 RECEPTORS
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The present invention relates to novel bicyclic thiazoles which are positive allosteric modulators of the metabotropic glutamate receptor subtype 5 (“mGluR5”) and which are useful for the treatment or prevention of disorders associated with glutamate dysfunction and diseases in which the mGluR5 subtype of receptors is involved. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes for preparing such compounds and compositions, and to the use of such compounds and compositions for the prevention and treatment of disorders in which mGluR5 is involved.
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Page/Page column 15
(2012/10/08)
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- BICYCLIC THIAZOLES AS ALLOSTERIC MODULATORS OF MGLUR5 RECEPTORS
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The present invention relates to novel bicyclic thiazoles of formula (I) which are positive allosteric modulators of the metabotropic glutamate receptor subtype 5 ("mGluR5") and which are useful for the treatment or prevention of disorders associated with glutamate dysfunction and diseases in which the mGluR5 subtype of receptors is involved. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes for preparing such compounds and compositions, and to the use of such compounds and compositions for the prevention and treatment of disorders in which mGluR5 is involved.
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Page/Page column 34
(2011/07/07)
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- BICYCLIC THIAZOLES AS ALLOSTERIC MODULATORS OF MGLUR5 RECEPTORS
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The present invention relates to novel bicyclic thiazoles of formula (I) which are positive allosteric modulators of the metabotropic glutamate receptor subtype 5 ("mGluR5") and which are useful for the treatment or prevention of disorders associated with glutamate dysfunction and diseases in which the mGluR5 subtype of receptors is involved. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes for preparing such compounds and compositions, and to the use of such compounds and compositions for the prevention and treatment of disorders in which mGluR5 is involved.
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Page/Page column 43
(2011/07/07)
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