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

  • Bioorg Med Chem Lett. 2011 Mar 15;21(6):1621-5. doi: 10.1016/j.bmcl.2011.01.113.
Karen A Atkinson  1 ,  Elena E Beretta ,  Janice A Brown ,  Mayda Castrodad ,  Yue Chen ,  Judith M Cosgrove ,  Ping Du ,  John Litchfield ,  Michael Makowski ,  Kelly Martin ,  Thomas J McLellan ,  Constantin Neagu ,  David A Perry ,  David W Piotrowski ,  Claire M Steppan ,  Richard Trilles
Affiliations
  • 1. Pfizer Global Research & Development, Groton Laboratories, Pfizer Inc., Groton, CT 06340, USA.
PMID: 21324691 DOI: 10.1016/j.bmcl.2011.01.113
Abstract

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.

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