Co- and terpolymers of N-isopropylacrylamide exhibit inverse temperature solubility in water with the polymer's lower critical solution temperature (LCST) being dependent on the polymer's microstructure and the concentration of salt in the water solvent. This solubility behavior has been used to prepare “smart” recoverable homogeneous catalysts and substrates. These catalysts' activity reversibly turns first off and then on as the temperature is first raised and then lowered due to changes in the polymer support's solubility. Such catalysts can be recovered by heating the aqueous solution or by adding brine. Catalysts prepared include both phosphine-ligated transition metal catalysts and acid catalysts. The transition metal catalysts are active in alkene hydrogenation, C−C coupling, and allylic substitution reactions. The acid catalysts are active in acetal hydrolysis. Substrates can be attached to these polymers and their activity likewise can be turned off and on by heating or cooling. Substrate activity on such supports can equal that of a low molecular weight analogue. NMR spectroscopic studies show that a vinyl group bound to PNIPAM has peaks whose line widths in 1H NMR spectroscopy are like those of a low molecular weight compound when a nine-carbon tether chain is used to attach the vinyl group to PNIPAM.

Structure-based drug design (SBDD) and polymer-assisted solution-phase (PASP) library synthesis were used to develop a series of pyrazinone inhibitors of the Tissue Factor/Factor VIIa (TF/VIIa) complex. The crystal structure of a tripeptide-alpha-ketothiazole complexed with TF/VIIa was utilized in a docking experiment to identify the pyrazinone core as a starting scaffold. The pyrazinone core could orient the substituents in the correct spatial arrangement to probe the S1, S2, and S3 pockets of the enzyme. A multistep PASP library synthesis was designed to prepare the substituted pyrazinones varying the P1, P2, and P3 moieties. Hundreds of pyrazinone TF/VIIa inhibitors were prepared and tested in several serine protease enzyme assays involved in the coagulation cascade. The inhibitors exhibited modest activity on TF/VIIa with excellent selectivity over thrombin (IIa) and Factor Xa. The structure-activity relationship of the pyrazinone inhibitors will be discussed and X-ray crystal structures of selected compounds complexed with the TF/VIIa enzyme will be described. This study ultimately led to the synthesis of compound 34, which exhibited 16 nM (IC50) activity on TF/VIIa with >6250 x selectivity vs Factor Xa and thrombin. This potent and highly selective inhibitor of TF/VIIa was chosen for preclinical, intravenous proof-of-concept studies to demonstrate the separation between antithrombotic efficacy and bleeding side effects in a nonhuman primate model of electrolytic-induced arterial thrombosis.

A new 1,4-dihydropyridine 5a, containing a cyano group at the C3 position, was recently reported to possess excellent mineralocorticoid receptor (MR) antagonist in vitro potency and no calcium channel-blocker (CCB) activity. In the present study, we report the structure-activity relationships of this novel series of cyano ester dihydropyridines that resulted in R6 substituted analogues with improved metabolic stability while maintaining excellent MR antagonist activity and selectivity against other nuclear receptors. Further structure optimization with the introduction of five-membered ring heterocycles at R6 resulted in compounds with excellent MR antagonist potency and a suitable pharmacokinetic profile. In vivo studies of a promising tool compound in the Dahl salt-sensitive rat model of hypertension showed similar blood pressure (BP) reduction as the steroidal MR antagonist eplerenone, providing proof-of-concept (POC) for a nonsteroidal, orally efficacious MR antagonist.

[reaction: see text] Fluoroacrylate polymer-bound hydrogenation catalysts are described. N-Acryloxysuccinimide-containing fluoroacrylate polymers were converted into phosphine ligands and subsequently into analogues of Wilkinson's catalyst by amidation of N-acryloxysuccinimide active ester residues and Rh exchange. The resulting catalysts have excellent activity and can be reused following fluorous biphasic liquid/liquid separation and extraction.

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