A novel class of 5-cyanopyrimidine-based inhibitors of p38alpha MAP kinase has been investigated. Analogues optimized through SAR iterations display low nanomolar enzymatic and cellular activity. The ...in vivo efficacy of this class of p38 inhibitors was demonstrated by 3a and 3b (>50% reduction in TNF levels when orally dosed at 5 mg/kg, 5 h prior to LPS administration in an acute murine model of inflammation). For 3a and 3b, the previously identified N-methoxybenzamide moiety (1) was replaced with N-(isoxazol-3-yl)benzamide, thereby providing increased metabolic stability. Cyanopyrimidine 3a demonstrated 100% oral bioavailability in mouse. High p38 kinase selectivity versus over 20 kinases was observed for analogue 3b. Direct hydrogen bonding of the cyano nitrogen of the 5-cyanopyrimidine core to the backbone NH of Met109 was confirmed by X-ray crystallographic analysis of 3a bound to p38alpha.
Two three-dimensional quantitative structure-activity relationship (3D-QSAR) methods, comparative molecular field analysis (CoMFA) and hypothetical active site lattice (HASL), were compared with ...respect to the analysis of a training set of 154 artemisinin analogues. Five models were created, including a complete HASL and two trimmed versions, as well as two CoMFA models (leave-one-out standard CoMFA and the guided-region selection protocol). Similar r2 and q2 values were obtained by each method, although some striking differences existed between CoMFA contour maps and the HASL output. Each of the four predictive models exhibited a similar ability to predict the activity of a test set of 23 artemisinin analogues, although some differences were noted as to which compounds were described well by either model.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
A series of substituted 2-(aminoheteroaryl)-thiazole-5-carboxamide analogs have been synthesized as novel, potent inhibitors of the Src-family kinase
p56
Lck. Among them, compound
2 displayed ...superior in vitro potency and excellent in vivo efficacy.
A series of substituted 2-(aminoheteroaryl)-thiazole-5-carboxamide analogs have been synthesized as novel, potent inhibitors of the Src-family kinase
p56
Lck. Among them, compound
2 displayed superior in vitro potency and excellent in vivo efficacy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
A series of structurally novel benzothiazole based small molecule inhibitors of p56
lck was prepared to elucidate their structure–activity relationships (SAR), selectivity and cell activity in the ...T-cell proliferation assay. BMS-350751 (
2) and BMS-358233 (
3) are identified as potent Lck inhibitors with excellent cellular activities against T-cell proliferation.
A series of structurally novel benzothiazole based small molecule inhibitors of p56
lck was prepared to elucidate their structure–activity relationships (SAR), selectivity and cell activity in the T-cell proliferation assay. BMS-350751 (
2) and BMS-358233 (
3) are identified as potent Lck inhibitors with excellent cellular activities against T-cell proliferation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
A novel series of 2-amino-5-carboxamidothiazoles were identified as inhibitors of Lck. Structure–activity studies demonstrate the structural requirements for potent Lck activity. Cyclopropylamide
11d ...is a potent Lck inhibitor having sub-micromolar activity in a PBL proliferation assay.
A novel series of 2-amino-5-carboxamidothiazoles were identified as inhibitors of Lck. Structure–activity studies demonstrate the structural requirements for potent Lck activity. Cyclopropylamide
11d is a potent Lck inhibitor having sub-micromolar activity in a PBL proliferation assay.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
A series of structurally novel benzothiazole based small molecule inhibitors of p56
lck were prepared to elucidate their structure–activity relationships (SARs), selectivity and cell activity in the ...T-cell proliferation assay. BMS-243117 (compound
2) is identified as a potent, and selective Lck inhibitor with good cellular activity (IC
50=1.1
μM) against T-cell proliferation.
A series of structurally novel benzothiazole based small molecule inhibitors of p56
lck was prepared to elucidate their structure–activity relationships (SARs), selectivity, and cell activity in the T-cell proliferation assay. BMS-243117 is identified as a potent and selective Lck inhibitor with good cellular activity against T-cell proliferation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Rational design, synthesis, and SAR studies of a novel class of benzothiazole based inhibitors of p38alpha MAP kinase are described. The issue of metabolic instability associated with vicinal phenyl, ...benzodthiazol-6-yl oxazoles/imidazoles was addressed by the replacement of the central oxazole or imidazole ring with an aminopyrazole system. The proposed binding mode of this new class of p38alpha inhibitors was confirmed by X-ray crystallographic studies of a representative inhibitor (6a) bound to the p38alpha enzyme.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
