Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 27, Issue 11, Pages 2296-2301Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2017.04.043
Keywords
M-4; Muscarinic acetylcholine receptor; Positive allosteric modulator (PAM); Non-human primate (NHP); Structure-Activity Relationship (SAR)
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Funding
- NIH via the NIH Roadmap Initiative [1X01 MH077607]
- William K. Warren Foundation
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This letter describes the further chemical optimization of the 5-amino-thieno(2,3-c]pyridazine series (VU0467154/VU0467485) of M-4 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. (C) 2017 Elsevier Ltd. All rights reserved.
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