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2,3-Disubstituted acrylamides as potent glucokinase activators
Achyutharao Sidduri1, Joseph S Grimsby, Wendy L Corbett
1Department of Discovery Chemistry, Roche Research Center, 340 Kingsland Street, Nutley, NJ 07110, USA. achyutharao.sidduri@roche.com
Bioorganic & Medicinal Chemistry Letters
|September 1, 2010
Summary
Researchers explored new glucokinase activators (GKAs) by replacing the chiral center in phenylacetamides with olefins. A novel acrylamide analog demonstrated significant glucose-lowering effects in rats.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Drug Discovery
Background:
- Phenylacetamide derivatives are established glucokinase activators (GKAs), with activity residing in the R-isomer.
- Exploring structural modifications is key to discovering novel therapeutic agents.
Purpose of the Study:
- To investigate novel glucokinase activators (GKAs) by replacing the chiral center of phenylacetamides with olefins.
- To evaluate the structure-activity relationship (SAR) of these new olefinic GKAs.
- To assess the in vivo efficacy of promising candidates.
Main Methods:
- Synthesis of a series of olefinic compounds as potential GKAs.
- Comparative analysis of SAR between olefinic and phenylacetamide GKAs.
- Pharmacokinetic and glucose-lowering effect evaluation in Wistar rats.
Main Results:
- Olefins represent a new class of GKAs, paralleling the SAR of saturated derivatives.
- The new GKA series exhibited greater tolerance for larger substituents at the R(2) region.
- A 2,3-disubstituted acrylamide analog showed good absorption and potent glucose-lowering effects in rats.
Conclusions:
- Olefinic compounds are a viable alternative to phenylacetamides as GKAs.
- Structural modifications can enhance GKA properties, offering new therapeutic avenues.
- The novel acrylamide analog warrants further investigation for diabetes treatment.
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