1451994-72-1Relevant academic research and scientific papers
Synthesis and Preliminary Evaluation of 11C-Labeled VU0467485/AZ13713945 and Its Analogues for Imaging Muscarinic Acetylcholine Receptor Subtype 4
Deng, Xiaoyun,Hatori, Akiko,Chen, Zhen,Kumata, Katsushi,Shao, Tuo,Zhang, Xiaofei,Yamasaki, Tomoteru,Hu, Kuan,Yu, Qingzhen,Ma, Longle,Wang, Gangqiang,Wang, Lu,Shao, Yihan,Josephson, Lee,Sun, Shaofa,Zhang, Ming-Rong,Liang, Steven
, p. 303 - 309 (2019/01/04)
Muscarinic acetylcholine receptors (mAChRs) have five distinct subunits (M1–M5) and are involved in the action of the neurotransmitter acetylcholine in the central and peripheral nervous system. Attributed to the promising clinical efficacy of xanomeline, an M1/M4-preferring agonist, in patients of schizophrenia and Alzheimer's disease, M1- or M4-selective mAChR modulators have been developed that target the topographically distinct allosteric sites. Herein we report the synthesis and preliminary evaluation of 11C-labeled positron emission tomography (PET) ligands based on a validated M4R positive allosteric modulator VU0467485 (AZ13713945) to facilitate drug discovery. [11C]VU0467485 and two other ligands were prepared in high radiochemical yields (>30 %, decay-corrected) with high radiochemical purity (>99 %) and high molar activity (>74 GBq μmol?1). In vitro autoradiography studies indicated that these three ligands possess moderate-to-high in vitro specific binding to M4R. Nevertheless, further physiochemical property optimization is necessary to overcome the challenges associated with limited brain permeability.
Discovery of VU0467485/AZ13713945: An M4 PAM Evaluated as a Preclinical Candidate for the Treatment of Schizophrenia
Wood, Michael R.,Noetzel, Meredith J.,Melancon, Bruce J.,Poslusney, Michael S.,Nance, Kellie D.,Hurtado, Miguel A.,Luscombe, Vincent B.,Weiner, Rebecca L.,Rodriguez, Alice L.,Lamsal, Atin,Chang, Sichen,Bubser, Michael,Blobaum, Anna L.,Engers, Darren W.,Niswender, Colleen M.,Jones, Carrie K.,Brandon, Nicholas J.,Wood, Michael W.,Duggan, Mark E.,Conn, P. Jeffrey,Bridges, Thomas M.,Lindsley, Craig W.
supporting information, p. 233 - 238 (2017/03/08)
Herein, we report the structure-activity relationships within a series of potent, selective, and orally bioavailable muscarinic acetylcholine receptor 4 (M4) positive allosteric modulators (PAMs). Compound 6c (VU0467485) possesses robust in vitro M4 PAM potency across species and in vivo efficacy in preclinical models of schizophrenia. Coupled with an attractive DMPK profile and suitable predicted human PK, 6c (VU0467485) was evaluated as a preclinical development candidate.
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.
