期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 27, 期 2, 页码 171-175出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2016.11.086
关键词
M-4; Muscarinic acetylcholine receptor; Positive allosteric modulator (PAM); Schizophrenia; Structure-activity relationship (SAR)
资金
- NIH [1X01 MH077607]
- Molecular Libraries Probe Center Network [U54MH084659, U01MH087965]
- William K. Warren Foundation
This letter describes the chemical optimization of a novel series of M-4 positive 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). (C) 2016 Elsevier Ltd. All rights reserved.
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