Design and synthesis of potent, orally-active DGAT-1 inhibitors containing a dioxino[2,3-d]pyrimidine core.
| Autor: | Dow RL; Pfizer Global Research and Development, Groton, CT 06340, USA. robert.l.dow@pfizer.com, Andrews M, Aspnes GE, Balan G, Michael Gibbs E, Guzman-Perez A, Karki K, Laperle JL, Li JC, Litchfield J, Munchhof MJ, Perreault C, Patel L |
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| Jazyk: | angličtina |
| Zdroj: | Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2011 Oct 15; Vol. 21 (20), pp. 6122-5. Date of Electronic Publication: 2011 Aug 12. |
| DOI: | 10.1016/j.bmcl.2011.08.028 |
| Abstrakt: | A novel series of potent DGAT-1 inhibitors was developed originating from the lactam-based clinical candidate PF-04620110. Incorporation of a dioxino[2,3-d]pyrimidine-based core afforded good alignment of pharmacophore features and resulted in improved passive permeability. Development of an efficient, homochiral synthesis of these targets facilitated confirmation of predictions regarding the stereochemical-dependence of DGAT-1 inhibition for this series. Compound 10 was shown to be a potent inhibitor of human DGAT-1 (10 nM) and to suppress triglyceride synthesis at oral doses of <3mg/kg. (Copyright © 2011 Elsevier Ltd. All rights reserved.) |
| Databáze: | MEDLINE |
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