期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 26, 期 13, 页码 3029-3033出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2016.05.010
关键词
M-4; Muscarinic acetylcholine receptor; Positive allosteric modulator (PAM); Schizophrenia; Structure-Activity Relationship (SAR)
资金
- NIH via the NIH Roadmap Initiative [1X01 MH077607]
- Molecular Libraries Probe Center Network [U54MH084512, U54MH084659]
- William K. Warren, Jr. and the William K. Warren Foundation
This Letter describes the chemical optimization of a novel series of M-4 positive allosteric modulators (PAMs) based on a 5,6-dimethyl-4-(piperidin-1-yl) thieno[2,3-d]pyrimidine core, identified from an MLPCN functional high-throughput screen. The HTS hit was potent and selective, but not CNS penetrant. Potency was maintained, while CNS penetration was improved (rat brain: plasma K-p = 0.74), within the original core after several rounds of optimization; however, the thieno[2,3-d]pyrimidine core was subject to extensive oxidative metabolism. Ultimately, we identified a 6-fluoroquinazoline core replacement that afforded good M-4 PAM potency, muscarinic receptor subtype selectivity and CNS penetration (rat brain:plasma K-p > 10). Moreover, this campaign provided fundamentally distinct M-4 PAM chemotypes, greatly expanding the available structural diversity for this exciting CNS target. (C) 2016 Elsevier Ltd. All rights reserved.
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