AI Article Synopsis
- The letter details the ongoing chemical optimization of the VU0453595 series, which are M1 positive allosteric modulators (PAMs) used for central nervous system (CNS) targets.
- Researchers explored new 5,6- and 6,6-heterobicyclic structures to replace the original core in VU453595, which led to compounds with improved potency and better CNS distribution.
- This research introduced a variety of new chemical structures for M1 PAMs that lack hydrogen-bond donors, significantly enhancing the structural diversity available for further CNS studies.
Article Abstract
This Letter describes the continued chemical optimization of the VU0453595 series of M1 positive allosteric modulators (PAMs). By surveying alternative 5,6- and 6,6-heterobicylic cores for the 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one core of VU453595, we found new cores that engendered not only comparable or improved M1 PAM potency, but significantly improved CNS distribution (Kps 0.3-3.1). Moreover, this campaign provided fundamentally distinct M1 PAM chemotypes, greatly expanding the available structural diversity for this valuable CNS target, devoid of hydrogen-bond donors.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082649 | PMC |
| http://dx.doi.org/10.1016/j.bmcl.2016.04.083 | DOI Listing |
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