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Novel,potent, selective,and metabolically stable stearoyl-CoA desaturase (SCD) inhibitors |
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| Authors: | Dmitry O. Koltun Eric Q. Parkhill Natalya I. Vasilevich Andrei I. Glushkov Timur M. Zilbershtein Alexei V. Ivanov Andrew G. Cole Ian Henderson Nathan A. Zautke Sandra A. Brunn Nevena Mollova Kwan Leung Jeffrey W. Chisholm Jeff Zablocki |
| Affiliation: | 1. Department of Medicinal Chemistry, CV Therapeutics, Inc., Palo Alto, CA 94304, USA;2. ASINEX Ltd., Moscow 123367, Russia;3. Department of Chemistry, Ligand Pharmaceuticals, Inc., Cranbury, NJ 08512, USA;4. Department of Pharmacological Sciences, CV Therapeutics, Inc., Palo Alto, CA 94304, USA;5. Department of Pre-Clinical Development, CV Therapeutics, Inc., Palo Alto, CA 94304, USA |
| Abstract: | We identified a series of structurally novel SCD (Δ9 desaturase) inhibitors via high-throughput screening and follow-up SAR studies. Modification of the central bicyclic scaffold has proven key to our potency optimization effort. The most potent analog (8g) had IC50 value of 50 pM in a HEPG2 SCD assay and has been shown to be metabolically stable and selective against Δ5 and Δ6 desaturases. |
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