Factor Xa inhibitory activities for a series of N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}sulfonamides with different P1 groups are described. These data provide insight into binding interactions within the S1 primary specificity pocket; rationales are presented for the derived SAR on the basis of electronic interactions through crystal structures of fXa-ligand complexes and molecular modeling studies. A good correlation between in vitro anticoagulant activities with lipophilicity and the extent of human serum albumin binding is observed within this series of potent fXa inhibitors. Pharmacokinetic profiles in rat and dog, together with selectivity over other trypsin-like serine proteases, identified 1f as a candidate for further evaluation.

The scope of the acid-mediated 3-component synthesis of thiadiazines was investigated. A selective functionalization of the six-membered heterocyclic core structure was accomplished by sequential alkylations, saponifications, and coupling reactions. Several new analogs of a dihydropyrimidinone Hsp70 chaperone agonist, MAL1-271, showed promising activity in a cell based model of Huntington’s disease.

The First Intramolecular Silene Diels-Alder Reactions. -A derivative of (Ia) with a methyl-substituent at the terminal double bond yields no cycloadduct under the presented conditions. -(CZYZEWSKI, M.; SELLARS, J. D.; GULIASHVILI, T.; TIBBELIN, J.; JOHNSTONE, L.; BOWER, J.; BOX, M.; DAVIES, R. D. M.; OTTOSSON, H.; STEEL*, P. G.; Chem. Commun. (Cambridge) 50 (2014) 22, 2919-2921, http://dx.doi.org/10.1039/c3cc49526d ; Dep. Chem., Univ. Durham, Durham DH1 3LE, UK; Eng.) -M. Tismer 28-189

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