AI Article Synopsis
- A new series of compounds called N-aryl pyrrolidinonyl oxadiazoles were found to act as positive allosteric modulators (PAMs) for mGluR5.
- Through optimization, the 12c (-) enantiomer was identified as a potent candidate with good properties for drug development, while the position of substitutions significantly influences whether they act as PAMs or negative allosteric modulators (NAMs).
- The optimal substitutions for enhancing PAM efficacy include para fluorine and meta chloro or methyl groups, highlighting a challenge in balancing potency and drug-like characteristics due to a sensitive switch between PAM and NAM activity.
Article Abstract
A novel series of N-aryl pyrrolidinonyl oxadiazoles were identified as mGluR5 positive allosteric modulators (PAMs). Optimization of the initial lead compound 6a led to the identification of the 12c (-) enantiomer as a potent compound with acceptable in vitro clearance, CYP, hERG and PK properties. Para substituted N-aryl pyrrolidinonyl oxadiazoles are mGluR5 PAMs while the meta and ortho substituted N-aryl pyrrolidinonyl oxadiazoles are negative allosteric modulators (NAMs). Para fluoro substitution on the N-aryl group and meta chloro or methyl substituents on the aryl oxadiazole moiety are optimal for mGluR5 PAM efficacy. The existence of an exquisitely sensitive 'PAM to NAM switch' within this chemotype making it challenging for simultaneous optimization of potency and drug-like properties.
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| http://dx.doi.org/10.1016/j.bmcl.2012.06.094 | DOI Listing |
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N-Aryl pyrrolidinonyl oxadiazoles as potent mGluR5 positive allosteric modulators.
Bioorg Med Chem Lett
September 2012
Chemical & Pharmacokinetic Sciences, Lundbeck Research USA, 215 College Road, Paramus, NJ 07652, USA.
Article Synopsis
- A new series of compounds called N-aryl pyrrolidinonyl oxadiazoles were found to act as positive allosteric modulators (PAMs) for mGluR5.
- Through optimization, the 12c (-) enantiomer was identified as a potent candidate with good properties for drug development, while the position of substitutions significantly influences whether they act as PAMs or negative allosteric modulators (NAMs).
- The optimal substitutions for enhancing PAM efficacy include para fluorine and meta chloro or methyl groups, highlighting a challenge in balancing potency and drug-like characteristics due to a sensitive switch between PAM and NAM activity.
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