3-Substituted gem-cyclohexane sulfone based gamma-secretase inhibitors for Alzheimer's disease: conformational analysis and biological activity.
ABSTRACT Previously, chemistry effort on the gem-cyclohexane series of gamma-secretase inhibitors has focused on the 4-position of the cyclohexane ring. Recently chemistry has been directed towards the 3-position and substitution here has also provided compounds with high gamma-secretase activity.
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ABSTRACT: Microsomal prostaglandin E(2) synthase-1 (mPGES-1) is a novel therapeutic target for the treatment of inflammation and pain. In the preceding letter, we detailed the discovery of clinical candidate PF-04693627, a potent mPGES-1 inhibitor possessing a novel benzoxazole structure. While PF-04693627 was undergoing further preclinical profiling, we sought to identify a back-up mPGES-1 inhibitor that differentiated itself from PF-04693627. The design, synthesis, mPGES-1 activity and in vivo PK of a novel set of substituted benzoxazoles are described herein. Also described is a conformation-based hypothesis for mPGES-1 activity based on the preferred conformation of the cyclohexane ring within this class of inhibitors.Bioorganic & medicinal chemistry letters 12/2012; · 2.65 Impact Factor
- Current Topics in Medicinal Chemistry 01/2008; 8(1):17-33. · 3.45 Impact Factor
- Annual Reports in Medicinal Chemistry - ANNU REP MED CHEM. 01/2007; 42:27-47.