1375754-06-5Relevant academic research and scientific papers
Enantioselective Synthesis of a Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 5 (mGluR5) Receptor via Dynamic Kinetic Resolution of α-Amino Ketones
González-Bobes, Francisco,Hanson, Ronald,Strotman, Neil,Guo, Zhiwei,Goswami, Animesh
, p. 2077 - 2082 (2016/07/16)
The concise synthesis of a pharmaceutical candidate is described. The chiral core of the molecule is assembled using an aza-benzoin condensation and a dynamic kinetic resolution (DKR) as the key reactions. This enables superb control of the regio-, diastereo- and enantioselectivity of the synthesis. Both biocatalysts and transition metal catalysts are remarkably effective in the key asymmetric reduction step. Similar approaches could be considered in the synthesis of other 1,2-amino alcohols where traditional approaches based on functionalization of alkenes, epoxides or aziridines may suffer from selectivity issues. (Figure presented.) .
Difluorocyclobutylacetylenes as positive allosteric modulators of mGluR5 with reduced bioactivation potential
Degnan, Andrew P.,Maxwell, Darrell,Balakrishnan, Anand,Brown, Jeffrey M.,Easton, Amy,Gulianello, Michael,Hanumegowda, Umesh,Hill-Drzewi, Melissa,Miller, Regina,Santone, Kenneth S.,Senapati, Arun,Shields, Eric E.,Sivarao, Digavalli V.,Westphal, Ryan,Whiterock, Valerie J.,Zhuo, Xiaoliang,Bronson, Joanne J.,Macor, John E.
supporting information, p. 5871 - 5876 (2016/12/06)
Schizophrenia is a serious illness that affects millions of patients and has been associated with N-methyl-D-aspartate receptor (NMDAR) hypofunction. It has been demonstrated that activation of metabotropic glutamate receptor 5 (mGluR5) enhances NMDA receptor function, suggesting the potential utility of mGluR5 positive allosteric modulators (PAMs) in the treatment of schizophrenia. Herein we describe the optimization of an mGluR5 PAM by replacement of a phenyl with aliphatic heterocycles and carbocycles as a strategy to reduce bioactivation in a biaryl acetylene chemotype. Replacement with a difluorocyclobutane followed by further optimization culminated in the identification of compound 32, a low fold shift PAM with reduced bioactivation potential. Compound 32 demonstrated favorable brain uptake and robust efficacy in mouse novel object recognition (NOR) at low doses.
Discovery and Preclinical Evaluation of BMS-955829, a Potent Positive Allosteric Modulator of mGluR5
Yang, Fukang,Snyder, Lawrence B.,Balakrishnan, Anand,Brown, Jeffrey M.,Sivarao, Digavalli V.,Easton, Amy,Fernandes, Alda,Gulianello, Michael,Hanumegowda, Umesh M.,Huang, Hong,Huang, Yanling,Jones, Kelli M.,Li, Yu-Wen,Matchett, Michele,Mattson, Gail,Miller, Regina,Santone, Kenneth S.,Senapati, Arun,Shields, Eric E.,Simutis, Frank J.,Westphal, Ryan,Whiterock, Valerie J.,Bronson, Joanne J.,MacOr, John E.,Degnan, Andrew P.
, p. 289 - 293 (2016/03/22)
Positive allosteric modulators (PAMs) of the metabotropic glutamate receptor subtype 5 (mGluR5) are of interest due to their potential therapeutic utility in schizophrenia and other cognitive disorders. Herein we describe the discovery and optimization of a novel oxazolidinone-based chemotype to identify BMS-955829 (4), a compound with high functional PAM potency, excellent mGluR5 binding affinity, low glutamate fold shift, and high selectivity for the mGluR5 subtype. The low fold shift and absence of agonist activity proved critical in the identification of a molecule with an acceptable preclinical safety profile. Despite its low fold shift, 4 retained efficacy in set shifting and novel object recognition models in rodents.
