Author: Zhang, Xiaofei ; Deng, Xiaoyun ; Shao, Yihan ; Josephson, Lee ; Yamasaki, Tomoteru ; Wang, Lu ; Shao, Tuo ; Zhang, Ming‐Rong ; Sun, Shaofa ; Kumata, Katsushi ; Liang, Steven ; Wang, Gangqiang ; Hatori, Akiko ; Yu, Qingzhen ; Ma, Longle ; Hu, Kuan ; Chen, Zhen

AbstractMuscarinic 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.

01 Jun 2017·Bioorganic & Medicinal Chemistry LettersQ4 · MEDICINE

Optimization of M 4 positive allosteric modulators (PAMs): The discovery of VU0476406, a non-human primate in vivo tool compound for translational pharmacology

Q4 · MEDICINE

Article

Author: Wood, Michael R ; Niswender, Colleen M ; Melancon, Bruce J ; Engers, Darren W ; Jones, Carrie K ; Nance, Kellie D ; Bubser, Michael ; Lamsal, Atin ; Brandon, Nicholas J ; Wu, Dedong ; Duggan, Mark E ; Chang, Sichen ; Cho, Hyekyung P ; Lindsley, Craig W ; Byers, Frank W ; Wood, Michael W ; Bridges, Thomas M ; Engelberg, Eileen M ; Conn, P Jeffrey ; Han, Changho ; Noetzel, Meredith J

This letter describes the further chemical optimization of the 5-amino-thieno[2,3-c]pyridazine series (VU0467154/VU0467485) of M₄ positive allosteric modulators (PAMs), developed via iterative parallel synthesis, culminating in the discovery of the non-human primate (NHP) in vivo tool compound, VU0476406 (8p). VU0476406 is an important in vivo tool compound to enable translation of pharmacodynamics from rodent to NHP, and while data related to a Parkinson's disease model has been reported with 8p, this is the first disclosure of the optimization and discovery of VU0476406, as well as detailed pharmacology and DMPK properties.

09 Feb 2017·ACS Medicinal Chemistry LettersQ3 · MEDICINE

Discovery of VU0467485/AZ13713945: An M₄ PAM Evaluated as a Preclinical Candidate for the Treatment of Schizophrenia

Q3 · MEDICINE

Article

Author: Nance, Kellie D. ; Wood, Michael R. ; Engers, Darren W. ; Conn, P. Jeffrey ; Rodriguez, Alice L. ; Lindsley, Craig W. ; Blobaum, Anna L. ; Bubser, Michael ; Niswender, Colleen M. ; Wood, Michael W. ; Weiner, Rebecca L. ; Melancon, Bruce J. ; Duggan, Mark E. ; Chang, Sichen ; Noetzel, Meredith J. ; Bridges, Thomas M. ; Poslusney, Michael S. ; Jones, Carrie K. ; Lamsal, Atin ; Luscombe, Vincent B. ; Brandon, Nicholas J. ; Hurtado, Miguel A.

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.

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Indication	Highest Phase	Country/Location	Organization	Date
Schizophrenia	Preclinical	United States	Vanderbilt University	20 Dec 2016
Schizophrenia	Preclinical	New Zealand	AstraZeneca PLC	20 Dec 2016

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