1451994-12-9Relevant academic research and scientific papers
Challenges in the development of an M4PAM in vivo tool compound: The discovery of VU0467154 and unexpected DMPK profiles of close analogs
Wood, Michael R.,Noetzel, Meredith J.,Poslusney, Michael S.,Melancon, Bruce J.,Tarr, James C.,Lamsal, Atin,Chang, Sichen,Luscombe, Vincent B.,Weiner, Rebecca L.,Cho, Hyekyung P.,Bubser, Michael,Jones, Carrie K.,Niswender, Colleen M.,Wood, Michael W.,Engers, Darren W.,Brandon, Nicholas J.,Duggan, Mark E.,Conn, P. Jeffrey,Bridges, Thomas M.,Lindsley, Craig W.
, p. 171 - 175 (2016/12/27)
This letter describes the chemical optimization of a novel series of M4positive allosteric modulators (PAMs) based on a 5-amino-thieno[2,3-c]pyridazine core, developed via iterative parallel synthesis, and culminating in the highly utilized rodent in vivo tool compound, VU0467154 (5). This is the first report of the optimization campaign (SAR and DMPK profiling) that led to the discovery of VU0467154, and details all of the challenges faced in allosteric modulator programs (steep SAR, species differences in PAM pharmacology and subtle structural changes affecting CNS penetration).
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 001034; 001036; 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.
