Development of a liver-targeted stearoyl-CoA desaturase (SCD) inhibitor (MK-8245) to establish a therapeutic window for the treatment of diabetes and dyslipidemia

  • J Med Chem. 2011 Jul 28;54(14):5082-96. doi: 10.1021/jm200319u.
Renata M Oballa  1 ,  Liette Belair ,  W Cameron Black ,  Kelly Bleasby ,  Chi Chung Chan ,  Carole Desroches ,  Xiaobing Du ,  Robert Gordon ,  Jocelyne Guay ,  Sebastien Guiral ,  Michael J Hafey ,  Emelie Hamelin ,  Zheng Huang ,  Brian Kennedy ,  Nicolas Lachance ,  France Landry ,  Chun Sing Li ,  Joseph Mancini ,  Denis Normandin ,  Alessandro Pocai ,  David A Powell ,  Yeeman K Ramtohul ,  Kathryn Skorey ,  Dan Sørensen ,  Wayne Sturkenboom ,  Angela Styhler ,  Deena M Waddleton ,  Hao Wang ,  Simon Wong ,  Lijing Xu ,  Lei Zhang
Affiliations
  • 1. Merck Frosst Centre for Therapeutic Research, 16711 TransCanada Highway, Kirkland, Québec H9H 3L1, Canada. [email protected]
PMID: 21661758 DOI: 10.1021/jm200319u
Abstract

The potential use of SCD inhibitors for the chronic treatment of diabetes and dyslipidemia has been limited by preclinical adverse events associated with inhibition of SCD in skin and eye tissues. To establish a therapeutic window, we embarked on designing liver-targeted SCD inhibitors by utilizing molecular recognition by liver-specific organic anion transporting polypeptides (OATPs). In doing so, we set out to target the SCD inhibitor to the organ believed to be responsible for the therapeutic efficacy (liver) while minimizing its exposure in the tissues associated with mechanism-based SCD depletion of essential lubricating lipids (skin and eye). These efforts led to the discovery of MK-8245 (7), a potent, liver-targeted SCD inhibitor with preclinical antidiabetic and antidyslipidemic efficacy with a significantly improved therapeutic window.

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