1451994-74-3Relevant academic research and scientific papers
Challenges in the development of an M4 PAM preclinical candidate: The discovery, SAR, and in vivo characterization of a series of 3-aminoazetidine-derived amides
Tarr, James C.,Wood, Michael R.,Noetzel, Meredith J.,Bertron, Jeanette L.,Weiner, Rebecca L.,Rodriguez, Alice L.,Lamsal, Atin,Byers, Frank W.,Chang, Sichen,Cho, Hyekyung P.,Jones, Carrie K.,Niswender, Colleen M.,Wood, Michael W.,Brandon, Nicholas J.,Duggan, Mark E.,Conn, P. Jeffrey,Bridges, Thomas M.,Lindsley, Craig W.
, p. 2990 - 2995 (2017)
This letter details the continued chemical optimization of a novel series of M4 positive allosteric modulators (PAMs) based on a 5-amino-thieno[2,3-c]pyridazine core by incorporating a 3-amino azetidine amide moiety. The analogs described within this work represent the most potent M4 PAMs reported for this series to date. The SAR to address potency, clearance, subtype selectivity, CNS exposure, and P-gp efflux are described. This work culminated in the discovery of VU6000918, which demonstrated robust efficacy in a rat amphetamine-induced hyperlocomotion reversal model at a minimum efficacious dose of 0.3?mg/kg.
SUBSTITUTED 5-AMINOTHIENO[2,3-C]PYRIDAZINE-6-CARBOXAMIDE ANALOGS AS POSITIVE ALLOSTERIC MODULATORS OF THE MUSCARINIC ACETYLCHOLINE RECEPTOR M4
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Paragraph 001041; 001044; 001146, (2013/09/12)
In one aspect, the invention relates to substituted 5-aminothieno[2,3-c]pyridazine-6- carboxamide analogs, derivatives thereof, and related compounds, which are useful as positive allosteric modulators of the muscarinic acetylcholine receptor M4 (mAChR M4); synthesis methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.
