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The design of conformationally restricted eight-membered ring diketones as transition state mimics of the mechanism of action of cyclotheonamides on serine proteases is described. Two target compounds are prepared from mutilin, derived from the natural product pleuromutilin. Compound 3 shows significant inhibition of plasmin and urokinase in enzyme rate assays, but an analogue 4 in which the amide moiety has been omitted does not. An X-ray crystal structure of the diketone 3 confirms the conformational predictions made by molecular modelling. [Copyright &y& Elsevier]

A novel series of 3,4-diaza-bicyclo[4.1.0]hept-4-en-2-ones were designed and synthesized as H 3 R analogs of irdabisant 6 . Separation of the isomers, assignment of the stereochemistry by crystallography, and detailed profiling of diastereomers 25 and 26 led to the identification of (1 R ,6 S )-5-{4-[3-(( R )-2-methyl-pyrrolidin-1-yl)propoxy]phenyl}-3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one 25 as a potential second generation H 3 R candidate. Diastereomer 25 had high H 3 R binding affinity, excellent selectivity, displayed potent H 3 R functional antagonism and robust wake-promoting activity in vivo, and showed acceptable pharmacokinetic and pharmaceutical profiles for potential further development. [ABSTRACT FROM AUTHOR]

The diastereoselective synthesis and biological activity of piperidine-3,4-diol and piperidine-3-ol-derived pyrrolotriazine inhibitors of anaplastic lymphoma kinase (ALK) are described. Although piperidine-3,4-diol and piperidine-3-ol derivatives showed comparable in vitro ALK activity, the latter subset of inhibitors demonstrated improved physiochemical and pharmacokinetic properties. Furthermore, the stereochemistry of the C3 and C4 centers had a marked impact on the in vivo inhibition of ALK autophosphorylation. Thus, trans -4-aryl-piperidine-3-ols ( 22 ) were more potent than the cis diastereomers ( 20 ). [ABSTRACT FROM AUTHOR]

In our continuing efforts to identify small molecule vitronectin receptor antagonists, we have discovered a series of phenylbutyrate derivatives, exemplified by 16, which have good potency and excellent oral bioavailability (approximately 100% in rats). This new series is derived conceptually from opening of the seven-membered ring of SB-265123. [Copyright &y& Elsevier]

Regioselective hydrogenation of enantiopure 3-substituted and 3,3-disubstituted aziridine 2-carboxylate esters affords β-amino acids and quaternary β-amino acids, respectively, in good yield. The aziridines are prepared via an aza-Darzens reaction of α-bromoenolates with enantiopure sulfinimines (N-sulfinyl imines) and by addition of Grignard reagents to 2H-azirine 2-carboxylate esters. [Copyright &y& Elsevier]