The discovery of tertiary-amine LXR agonists with potent cholesterol efflux activity in macrophages.

The liver X receptors (LXR) play a key role in cholesterol homeostasis and lipid metabolism. SAR studies around tertiary-amine lead molecule 2, an LXR full agonist, revealed that steric and conformational changes to the acetic acid and propanolamine groups produce dramatic effects on agonist efficacy and potency. The new analogs possess good functional activity, demonstrating the ability to upregulate LXR target genes, as well as promote cholesterol efflux in macrophages.

Development of dihydropyridone indazole amides as selective Rho-kinase inhibitors.

Rho kinase (ROCK1) mediates vascular smooth muscle contraction and is a potential target for the treatment of hypertension and related disorders. Indazole amide 3 was identified as a potent and selective ROCK1 inhibitor but possessed poor oral bioavailability. Optimization of this lead resulted in the discovery of a series of dihydropyridones, exemplified by 13, with improved pharmacokinetic parameters relative to the initial lead.

Discovery of aminofurazan-azabenzimidazoles as inhibitors of Rho-kinase with high kinase selectivity and antihypertensive activity.

The discovery, proposed binding mode, and optimization of a novel class of Rho-kinase inhibitors are presented. Appropriate substitution on the 6-position of the azabenzimidazole core provided subnanomolar enzyme potency in vitro while dramatically improving selectivity over a panel of other kinases. Pharmacokinetic data was obtained for the most potent and selective examples and one (6n) has been shown to lower blood pressure in a rat model of hypertension.

Evaluation of mass spectrometric methods applicable to the direct analysis of non-peptide bead-bound combinatorial libraries.

Electrospray, matrix-assisted laser desorption, and time-of-flight secondary ion mass spectrometry have been explored as possible methods for the identification of active members of molecular combinatorial libraries. All three methods are found to yield accurate molecular weight information about a target molecule angiotensin II antagonist synthesized on a 40-microns polystyrene bead. Structural identification is also possible by accurate mass measurements to eliminate candidate structures with the same nominal mass and by analysis of the fragmentation patterns.

Potent nonpeptide angiotensin II receptor antagonists. 2. 1-(Carboxybenzyl)imidazole-5-acrylic acids.

The further evolution of the imidazole-5-acrylic acid series of nonpeptide angiotensin II receptor antagonists is detailed (for Part 1, see: J. Med. Chem.