Derek C Cole

..The polystyrene bound sulfoxide may be used in Swern oxidation reactions, and the used reagent may be regenerated by oxidation with tert-butylhydrogen peroxide...

..5-fold) gamma-secretase inhibitor (S)-N-(5-chlorothiophene-2-sulfonyl)-beta,beta-diethylalaninol 7.b.2 (Abeta(40/42) EC(50)=28 nM), which is efficacious in reduction of Abeta production in vivo...

..Compound 4p also inhibited IL-2 production in antiCD3/anti-CD28 activated T cells enriched from splenocytes...

..Optimization of the physical properties of the series led to (S)-6n, with improved brain to plasma exposure and efficacy in both water intake and novel object recognition models...

..a.1). We report here the initial hit-to-lead optimization of this hit and the SAR around the aryl groups occupying the S(1) and S(2') pockets leading to submicromolar BACE-1 inhibitors...

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..4 and 3.0 nM affinity, respectively, and antagonized the production of adenylate cyclase at sub-nanomolar concentrations...

..Within this class, several of the (R)-enantiomers were potent agonists having EC(50) values of 1 nM or less and functioning as full agonists while the (S)-enantiomers displayed moderate antagonist activity...

..Several of the N1-arylsulfonyl-3-(1-methylpyrrolidin-2-ylmethyl)-1H-indole derivatives behave as very potent antagonists ((S)-11r, (S)-11t; IC50 = 0.8, 1.0 nM)...

..Structure-based optimization led to the identification of potent analogs, such as 10d (BACE1 IC(50) = 110 nM)...

..This study led to the discovery of compound 12d, which had an IC(50) value of 18nM for the inhibition of PKCtheta...

..Further side chain modification afforded the potent Notch-1-sparing GSI begacestat (5), which was selected for development for the treatment of Alzheimer's disease...

..Lead optimization using structure-based focused libraries led to the identification of low nanomolar BACE1 inhibitors such as 20b with substituents which extend from the S(1) to the S(3) pocket...

..These pyrazolopyrimidines represent an exciting new series of mTOR-selective inhibitors with potential for development for cancer therapy...

..We report here the optimization of guanidinyl functional group substituents on 1, leading to potent submicromolar BACE-1 inhibitors...

..Lead optimization studies led to the discovery of analog 8e with improved gamma-secretase inhibitory potency and Notch-sparing selectivity...

..Optimization of the groups at C-4 and C-2 led to analog 29, which has an IC(50) value of 7.5nM for the inhibition of PKCtheta...

..This compound also reduced adjunctive drinking behavior in the rat schedule-induced polydipsia assay, possibly predictive of efficacy in obsessive compulsive disorder and other anxiety related disorders...

..The lead compounds in this series are selective and block C5a binding, C5a-promoted calcium flux in human neutrophils with nanomolar potency...

..Preliminary screening of a library of 1280 pharmaceutically active compounds identified inhibitors with novel chemical scaffolds. This assay will be a powerful tool for target validation and drug lead identification and characterization...

..This work provides the experimentalist with complimentary synthetic pathways that afford either the pyrimidin-7-one or the pyrimidin-5-one regioisomer...

..Compound 8 also inhibited cytokine induced JAK activation but did not inhibit BCR-ABL activated STAT5 phosphorylation in K562 cells...

..Thus, the FLIPR assay described here can be used to assess, compare, and rank the potency and selectivity of inhibitors of Itk and Btk kinases...

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