Discovery of 3-OH-3-methylpipecolic hydroxamates: potent orally active inhibitors of aggrecanase and MMP-13.
Basic Information
ID: ALA1139577
Journal: Bioorg Med Chem Lett
Title: Discovery of 3-OH-3-methylpipecolic hydroxamates: potent orally active inhibitors of aggrecanase and MMP-13.
Authors: Noe MC, Natarajan V, Snow SL, Wolf-Gouveia LA, Mitchell PG, Lopresti-Morrow L, Reeves LM, Yocum SA, Otterness I, Bliven MA, Carty TJ, Barberia JT, Sweeney FJ, Liras JL, Vaughn M.
Abstract: A series of 3-hydroxy-3-methylpipecolic hydroxamate inhibitors of MMP-13 and aggrecanase was designed based on the observation of increased aggrecanase activity with substitution at the 3-position of the piperidine ring. Potency versus aggrecanase was optimized by modification of the benzyloxyarylsulfonamide group that binds in the S1' pocket. These compounds also possess markedly improved bioavailability and lower metabolic clearance compared to analogous 3,3-dimethyl-5-hydroxypipecolic hydroxamates. These improvements are attributed to lowered lipophilicity proximal to the metabolically labile hydroxamic acid. Synthesis, structure activity relationships, and in vivo efficacy data are described.
CiteXplore: 15953722
DOI: 10.1016/j.bmcl.2005.05.037
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