Recent efforts to identify treatments for myocardial ischemia reperfusion injury have resulted in the discovery of a novel series of highly potent α,α-disubstituted amino acid-based arginase inhibitors. The lead candidate, (R)-2-amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic acid, compound 9, inhibits human arginases I and II with IC50s of 223 and 509 nM, respectively, and is active in a recombinant cellular assay overexpressing human arginase I (CHO cells). It is 28% orally bioavailable and significantly reduces the infarct size in a rat model of myocardial ischemia/reperfusion injury. Herein, we report the design, synthesis, and structure-activity relationships (SAR) for this novel series of inhibitors along with pharmacokinetic and in vivo efficacy data for compound 9 and X-ray crystallography data for selected lead compounds cocrystallized with arginases I and II.

We have developed a modification of the Miyaura arylboronate synthesis(1a) by substituting a ligandless palladium catalyst for PdCl(2)(dppf). Palladium acetate, free of ligand, was found highly effective for such coupling reactions. This modified procedure is advantageous over the original Miyaura synthesis in ease of workup, catalyst removal, and low catalyst cost. Furthermore, the boronates formed in this manner can be used directly for Suzuki coupling reactions in a one-pot fashion. The biaryl products have improved impurity profiles and reduced heavy metal contamination.

A highly efficient diastereoselective, carboxylate-directed homogeneous hydrogenation of cyclic olefins with use of Wilkinson's catalyst is described. Under the optimized reaction conditions, better than 99% de was achieved. The experimental protocol is very simple and readily amenable to scale-up. [reaction: see text]

The monoglucuronides and sulfates of epicatechin, 3'-O-methylepicatechin, and 4'-O-methylepicatechin, respectively, were synthesized as authentic bioanalytical standards. Reversed-phase HPLC methods capable of baseline separation of the glucuronides and sulfates have been developed. Both the epicatechin glucuronides and sulfates were stable in the solid state when stored under ambient conditions and in aqueous solution when stored refrigerated. These results should prove invaluable to the research community as analytical standards as well as in future studies of the biological and pharmacological effects of epicatechin in humans.

Polyhaloanilines bearing an ortho halogen atom undergo smooth nucleophilic aromatic substitution reactions with anionic sulfur nucleophiles at relatively mild temperatures (95-120 degrees C). These reactions are very efficient and highly ortho-selective. With potassium/sodium O-ethyl xanthate as a nucleophile, subsequent cyclization follows to afford halogenated 2(3H)-benzothiazolethiones (2-mercaptobenzothiazoles) in high yields.