We report the design and discovery of a 2-aminobenzimidazole-based series of potent and highly selective p38alphainhibitors. The lead compound 1 had low-nanomolar activity in both ATP competitive enzyme binding and inhibition of TNFalpha release in macrophages. Compound 18 showed excellent pharmacokinetics properties and oral activity in the rat collagen induced arthritis model compared with other p38 reference compounds. A SAR strategy to address CyP3A4 liability is also described.

(+)-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (1), also known as LY354740, is a highly potent and selective agonist for group II metabotropic glutamate receptors (mGlu receptors 2 and 3) tested in clinical trials. It has been shown to block anxiety in the fear-potentiated startle model. Its relatively low bioavailability in different animal species drove the need for an effective prodrug form that would produce a therapeutic response at lower doses for the treatment of anxiety disorders. We have investigated the increase of intestinal absorption of this compound by targeting the human peptide transporter hPepT1 for active transport of di- and tripeptides derived from 1. We have found that oral administration of an N dipeptide derivative of 1 (12a) in rats shows up to an 8-fold increase in drug absorption and a 300-fold increase in potency in the fear-potentiated startle model in rats when compared with the parent drug 1.

The anti-proliferative activity of acylated heterocyclic sulfonamides is described in Vascular Endothelial Growth Factor-dependent Human Umbilical Vascular Endothelial Cells (VEGF-HUVEC) and in HCT116 tumor cells in a soft agar diffusion assay.

A new strategy was developed for the enantiospecific synthesis of aspidosperma alkaloids. The key steps involve a novel ketene-lactonization reaction of a chiral vinyl sulfoxide to efficiently set up the quaternary carbon center, and a tandem Michael addition-alkylation reaction sequence to form the polycyclic core structure. This new strategy was employed in the total synthesis of natural product (+)-aspidospermidine.

The first potent inhibitors of glutamate racemase (MurI) enzyme that show whole cell antibacterial activity are described. Optically pure 4-substituted D-glutamic acid analogues with (2R,4S) stereochemistry and bearing aryl-, heteroaryl-, cinnamyl-, or biaryl-methyl substituents represent a novel class of glutamate racemase inhibitors. Exploration of the D-Glu core led to the identification of lead compounds (-)-8 and 10. 2-Naphthylmethyl derivative 10 was found to be a potent competitive inhibitor of glutamate racemase activity (K-i = 16 nM, circular dichroism assay; IC50 = 0.1 mug/mL high-performance liquid chromatography (HPLC) assay). Thorough structure-activity relationship (SAR) studies led to benzothienyl derivatives such as 69 and 74 with increased potency (IC50 = 0.036 and 0.01 mug/mL, respectively, HPLC assay). These compounds showed potent whole cell antibacterial activity against S. pneumoniae PN-R6, and good correlation with the enzyme assay. Compounds 69, 74 and biaryl derivative 52 showed efficacy in an in vivo murine thigh infection model against Streptococcus pneumoniae. Data described herein suggest that glutamate racemase may be a viable target for developing new antibacterial agents.