AI Article Synopsis
- - The letter discusses the development of new M positive allosteric modulators (PAMs) using a unique benzomorpholine structure, created through a parallel synthesis approach.
- - It highlights the optimization process that led to the discovery of the rodent tool compound VU0486846 (7), which has no adverse effects.
- - The report outlines the challenges encountered in the optimization campaign, including structure-activity relationship (SAR) and drug metabolism and pharmacokinetics (DMPK) profiling, focusing on the impact of small structural changes on properties like CNS penetration.
Article Abstract
This letter describes the chemical optimization of a new series of M positive allosteric modulators (PAMs) based on a novel benzomorpholine core, developed via iterative parallel synthesis, and culminating in the highly utilized rodent in vivo tool compound, VU0486846 (7), devoid of adverse effect liability. This is the first report of the optimization campaign (SAR and DMPK profiling) that led to the discovery of VU0486846 and details all of the challenges faced in allosteric modulator programs (both steep and flat SAR, as well as subtle structural changes affecting CNS penetration and overall physiochemical and DMPK properties).
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6427922 | PMC |
| http://dx.doi.org/10.1016/j.bmcl.2018.05.009 | DOI Listing |
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Article Synopsis
- - The letter discusses the development of new M positive allosteric modulators (PAMs) using a unique benzomorpholine structure, created through a parallel synthesis approach.
- - It highlights the optimization process that led to the discovery of the rodent tool compound VU0486846 (7), which has no adverse effects.
- - The report outlines the challenges encountered in the optimization campaign, including structure-activity relationship (SAR) and drug metabolism and pharmacokinetics (DMPK) profiling, focusing on the impact of small structural changes on properties like CNS penetration.
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