Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 27, Issue 13, Pages 2990-2995Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2017.05.014
Keywords
M4; Muscarinic acetylcholine receptor; Positive allosteric modulator (PAM); Schizophrenia; Azetidine
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Funding
- William K. Warren, Jr. and the William K. Warren Foundation
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This letter details the continued chemical optimization of a novel series of M4 positive allosteric modulators (PAMs) based on a 5-amino-thieno[2,3-c] pyridazine core by incorporating a 3-amino azetidine amide moiety. The analogs described within this work represent the most potent M4 PAMs reported for this series to date. The SAR to address potency, clearance, subtype selectivity, CNS exposure, and Pgp efflux are described. This work culminated in the discovery of VU6000918, which demonstrated robust efficacy in a rat amphetamine-induced hyperlocomotion reversal model at a minimum efficacious dose of 0.3 mg/kg. (C) 2017 Elsevier Ltd. All rights reserved.
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