Further optimization of the M5 NAM MLPCN probe ML375: tactics and challenges
Research output: Contribution to journal › Journal article › Research › peer-review
This Letter describes the continued optimization of the MLPCN probe ML375, a highly selective M5 negative allosteric modulator (NAM), through a combination of matrix libraries and iterative parallel synthesis. True to certain allosteric ligands, SAR was shallow, and the matrix library approach highlighted the challenges with M5 NAM SAR within in this chemotype. Once again, enantiospecific activity was noted, and potency at rat and human M5 were improved over ML375, along with slight enhancement in physiochemical properties, certain in vitro DMPK parameters and CNS distribution. Attempts to further enhance pharmacokinetics with deuterium incorporation afforded mixed results, but pretreatment with a pan-P450 inhibitor (1-aminobenzotriazole; ABT) provided increased plasma exposure.
Original language | English |
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Journal | Bioorganic & Medicinal Chemistry Letters |
Volume | 25 |
Issue number | 3 |
Pages (from-to) | 690-4 |
Number of pages | 5 |
ISSN | 0960-894X |
DOIs | |
Publication status | Published - 1 Feb 2015 |
Externally published | Yes |
Bibliographical note
Copyright © 2014 Elsevier Ltd. All rights reserved.
- Allosteric Regulation, Animals, Brain/metabolism, Half-Life, Humans, Imidazoles/chemistry, Indoles/chemistry, Microsomes, Liver/metabolism, Protein Binding, Rats, Receptor, Muscarinic M5/chemistry, Structure-Activity Relationship
Research areas
ID: 213599333