An overview of patented small molecule stearoyl coenzyme-A desaturase inhibitors (2009 - 2013)

Stearoyl coenzyme-A desaturase (SCD) is a critical lipogenic enzyme that converts a range of unsaturated lipids to their corresponding monounsaturated fatty acids. Genetic and enzyme-knockdown experiments have suggested an important role of SCD1 in the regulation of various metabolic disorders. With the prognostication that SCD-inhibition may serve to remediate various metabolic diseases, several pharmaceutical companies have embarked on the development of small-molecule SCD-inhibitors, with over 100 patent applications by 17 companies being reported to date.

Recent progress on the development of SCD-inhibitors, including preclinical efficacy and safety are reviewed. Strategies toward overcoming systemic adverse events and the establishment of a suitable therapeutic margin for clinical studies are discussed.

Preclinically, SCD-inhibition leads to reductions in body-weight gain, improvements in glucose clearance and improved liver-lipid profile. However, chronic SCD inhibition in skin and eye-lubricating glands results in undesirable adverse events. Several strategies to overcome these findings have been described, including alternative administration routes for acne or oncology applications, use of potent and rapidly cleared compounds and SCD-inhibitors with a liver-targeted tissue distribution profile. The attainment of sufficient therapeutic margin and robust efficacy for therapeutic applications in humans remains a major frontier for SCD-inhibitors.