Further optimization of the M 5 NAM MLPCN probe ML375: Tactics and challenges
Bioorganic & Medicinal Chemistry Letters, ISSN: 0960-894X, Vol: 25, Issue: 3, Page: 690-694
2015
- 19Citations
- 17Captures
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Example: if you select the 1-year option for an article published in 2019 and a metric category shows 90%, that means that the article or review is performing better than 90% of the other articles/reviews published in that journal in 2019. If you select the 3-year option for the same article published in 2019 and the metric category shows 90%, that means that the article or review is performing better than 90% of the other articles/reviews published in that journal in 2019, 2018 and 2017.
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Metrics Details
- Citations19
- Citation Indexes19
- CrossRef19
- 17
- Captures17
- Readers17
- 17
Article Description
This Letter describes the continued optimization of the MLPCN probe ML375, a highly selective M 5 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 M 5 NAM SAR within in this chemotype. Once again, enantiospecific activity was noted, and potency at rat and human M 5 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.
Bibliographic Details
http://www.sciencedirect.com/science/article/pii/S0960894X1401289X; http://dx.doi.org/10.1016/j.bmcl.2014.11.082; http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84920742471&origin=inward; http://www.ncbi.nlm.nih.gov/pubmed/25542588; https://linkinghub.elsevier.com/retrieve/pii/S0960894X1401289X
Elsevier BV
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