期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 26, 期 15, 页码 3822-3825出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2016.04.083
关键词
M-1; Muscarinic acetylcholine receptor; Positive allosteric modulator (PAM); CNS penetration; Structure-activity relationship (SAR)
资金
- NIH via the National Institute of Mental Health [2RO1MH082867, 5R01MH073676, 1U19MH10 6839, 1U01MH087965]
- William K. Warren Foundation
- VISP program
This Letter describes the continued chemical optimization of the VU0453595 series of M-1 positive allosteric modulators (PAMs). By surveying alternative 5,6- and 6,6-heterobicylic cores for the 6,7-dihy-dro-5H-pyrrolo[3,4-b]pyridine-5-one core of VU453595, we found new cores that engendered not only comparable or improved M-1 PAM potency, but significantly improved CNS distribution (K(p)s 0.3-3.1). Moreover, this campaign provided fundamentally distinct M-1 PAM chemotypes, greatly expanding the available structural diversity for this valuable CNS target, devoid of hydrogen-bond donors. (C) 2016 Elsevier Ltd. All rights reserved.
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