N-benzylimidazole carboxamides as potent, orally active stearoylCoA desaturase-1 inhibitors.


A potent, small molecule inhibitor with a favorable pharmacokinetic profile to allow for sustained SCD inhibition in vivo was identified. Starting from a low MW acyl guanidine (5a), identified with a RapidFire High-Throughput Mass Spectrometry (RF-MS) assay, iterative library design was used to rapidly probe the amide and tail regions of the molecule. Singleton synthesis was used to probe core changes. Biological evaluation of a SCD inhibitor (5b) included in vitro potency at SCD-1 and in vivo modulation of the plasma desaturation index (DI) in rats on a low essential fatty acid (LEFA) diet. In addition to dose-dependent decrease in DI, effects on rodent ocular tissue were noted. Therefore, in rat, these SCD inhibitors only recapitulate a portion of phenotype exhibited by the SCD-1 knockout mouse.

DOI: 10.1016/j.bmcl.2011.01.113

Cite this paper

@article{Atkinson2011NbenzylimidazoleCA, title={N-benzylimidazole carboxamides as potent, orally active stearoylCoA desaturase-1 inhibitors.}, author={Karen A Atkinson and Elena Beretta and Janice A. Brown and Mayda Castrodad and Yue Chen and Judith M Cosgrove and Ping Yan Du and John Litchfield and Michael R Makowski and Kelly A Martin and Thomas J McLellan and Constantin Neagu and David A. Perry and David W. Piotrowski and Claire M. Steppan and Richard V Trilles}, journal={Bioorganic & medicinal chemistry letters}, year={2011}, volume={21 6}, pages={1621-5} }