Richard B. Sulsky

Treatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2

Adipocyte fatty-acid-binding protein, aP2 (FABP4) is expressed in adipocytes and macrophages, and integrates inflammatory and metabolic responses. Studies in aP2-deficient mice have shown that this lipid chaperone has a significant role in several aspects of metabolic syndrome, including type 2 diabetes and atherosclerosis. Here we demonstrate that an orally active small-molecule inhibitor of aP2 is an effective therapeutic agent against severe atherosclerosis and type 2 diabetes in mouse models. In macrophage and adipocyte cell lines with or without aP2, we also show the target specificity of this chemical intervention and its mechanisms of action on metabolic and inflammatory pathways. Our findings demonstrate that targeting aP2 with small-molecule inhibitors is possible and can lead to a new class of powerful therapeutic agents to prevent and treat metabolic diseases such as type 2 diabetes and atherosclerosis.

Dual metalloprotease inhibitors. II. Effect of substitution and stereochemistry on benzazepinone based mercaptoacetyls

Abstract A structure-activity study of dual-acting ACE/NEP inhibitor 1A was initiated in order to ascertain what parameters effect in vitro activity versus ACE and NEP. Unlike NEP, ACE was found to be remarkably tolerant to a wide variety of permutations with respect to both the lactam nucleus and the pharmacophore side chain.

Alkylation of n-benzyloxyureas and carbamates

Abstract N-Benzyloxyureas and orthogonally protected N-hydroxycarbamates can be alkylated in high yields and subsequently deprotected to provide N-alkyl hydroxyureas and hydroxylamines.

Reductions in log P improved protein binding and clearance predictions enabling the prospective design of cannabinoid receptor (CB1) antagonists with desired pharmacokinetic properties.

Several strategies have been employed to reduce the long in vivo half-life of our lead CB1 antagonist, triazolopyridazinone 3, to differentiate the pharmacokinetic profile versus the lead clinical compounds. An in vitro and in vivo clearance data set revealed a lack of correlation; however, when compounds with <5% free fraction were excluded, a more predictable correlation was observed. Compounds with log P between 3 and 4 were likely to have significant free fraction, so we designed compounds in this range to give more predictable clearance values. This strategy produced compounds with desirable in vivo half-lives, ultimately leading to the discovery of compound 46. The progression of compound 46 was halted due to the contemporaneous marketing and clinical withdrawal of other centrally acting CB1 antagonists; however, the design strategy successfully delivered a potent CB1 antagonist with the desired pharmacokinetic properties and a clean off-target profile.

Synthetic routes for the generation of 7,7-dialkyl azepin-2-ones

Abstract Three diverse synthetic routes to C-7 dialkylated and spiro-alkylated azepinones are described. Compounds of this type may be used as conformationally restricted dipeptide surrogates. Additionally, the chiral synthesis of novel cyclopropanated lysine derivative 29 is demonstrated.