1451996-10-3Relevant academic research and scientific papers
Challenges in the development of an M4 PAM preclinical candidate: The discovery, SAR, and biological characterization of a series of azetidine-derived tertiary amides
Tarr, James C.,Wood, Michael R.,Noetzel, Meredith J.,Melancon, Bruce J.,Lamsal, Atin,Luscombe, Vincent B.,Rodriguez, Alice L.,Byers, Frank W.,Chang, Sichen,Cho, Hyekyung P.,Engers, Darren W.,Jones, Carrie K.,Niswender, Colleen M.,Wood, Michael W.,Brandon, Nicholas J.,Duggan, Mark E.,Jeffrey Conn,Bridges, Thomas M.,Lindsley, Craig W.
, p. 5179 - 5184 (2017/11/03)
Herein we describe the continued optimization of M4 positive allosteric modulators (PAMs) within the 5-amino-thieno[2,3-c]pyridazine series of compounds. In this letter, we disclose our studies on tertiary amides derived from substituted azetidines. This series provided excellent CNS penetration, which had been challenging to consistently achieve in other amide series. Efforts to mitigate high clearance, aided by metabolic softspot analysis, were unsuccessful and precluded this series from further consideration as a preclinical candidate. In the course of this study, we found that potassium tetrafluoroborate salts could be engaged in a tosyl hydrazone reductive cross coupling reaction, a previously unreported transformation, which expands the synthetic utility of the methodology.
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 001049; 001052; 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.
