期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 28, 期 12, 页码 2175-2179出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2018.05.009
关键词
M-1; Muscarinic acetylcholine receptor; Positive allosteric modulator (PAM); Schizophrenia; Structure-Activity Relationship (SAR)
资金
- NIH
- NIMH [MH082867, MH106839]
- William K. Warren Foundation
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT [U54HD083211] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF MENTAL HEALTH [R01MH082867, U19MH106839] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R01AG051626] Funding Source: NIH RePORTER
This letter describes the chemical optimization of a new series of M-1 positive allosteric modulators (PAMs) based on a novel benzomorpholme core, developed via iterative parallel synthesis, and culminating in the highly utilized rodent in vivo tool compound, VU0486846 (7), devoid of adverse effect liability. This is the first report of the optimization campaign (SAR and DMPK profiling) that led to the discovery of VU0486846 and details all of the challenges faced in allosteric modulator programs (both steep and flat SAR, as well as subtle structural changes affecting CNS penetration and overall physiochemical and DMPK properties).
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据