Phenyl-substituted analogues of 2-(phenylmethyl)sulfonylpyridine 1-oxide preemergent herbicides were examined in order to determine quantitative relationships between structure and activity against ...the following three weed species: switch grass (Panicum virgatum L.), barnyard grass (Echinochloa crusgalli L. Beauv.), and green foxtail (Setaria viridis L. Beauv.). Analogues were chosen to provide maximum parameter orthogonality. Regression analysis yielded structure-activity relationships wherein the most significant substituent parameters associated with herbicidal activity were found to be the partition coefficient (pi), the molar refractivity (MR), and two indicator variables, Z (denoting the presence of an alpha-methyl group) and H (denoting an ortho substituent capable of hydrogen bonding). For green foxtail, the structure-activity relationship was found to be: -log ED50 = 0.43 pi -0.052MR + 0.50H + 0.24Z + 0.61, where ED50 is expressed in moles per acre. The regression equations were found to explain 79-93% of the bioactivity for the three weed species studied. It was further shown that these equations represent the best possible correlations within the limitations of the biological data.
A novel structural class of p38alpha MAP kinase inhibitors has been identified via iterative SAR studies of a focused deck screen hit. Optimization of the lead series generated 6e, BMS-640994, a ...potent and selective p38alpha inhibitor that is orally efficacious in rodent models of acute and chronic inflammation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
We have identified a novel series of 1,5-imidazoquinoxalines as inhibitors of Lck with excellent potency (IC
50s<5
nM) as well as good cellular activity against T-cell proliferation (IC
50s<1
μM). ...Structure–activity studies demonstrate the requirement for the core heterocycle in addition to an optimal 2,6-disubstituted aniline group.
We have identified a novel series of 1,5-imidazoquinoxalines as inhibitors of Lck with excellent potency (IC
50s<5
nM) as well as good cellular activity against T-cell proliferation (IC
50s<1
μM). Structure–activity studies demonstrate the requirement for the core heterocycle in addition to an optimal 2,6-disubstituted aniline group.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The phosphonate analogues of methionine and buthionine sulfoximide were synthesized by the action of NaN
3
on the corresponding sulfoxides. Analogues 3 and 4 were prepared to determine the effect of ...altering the carboxyl portion of known inhibitors in the glutamate synthase cycle. Results of biological testing revealed that 3 and 4 did not posses the potency found with buthionine and methionine sulfoximide in cellular systems. However 3 was found to be an effective and irreversible inhibitor of glutamine synthetase.
Synthesis of a series of alpha-hydroxythiol esters made available, for the first time, product-like molecules that were evaluated as inhibitors of the enzyme glyoxalase I and as potential antitumor ...agents. All the alpha-hydroxythiol esters tested were competitive inhibitors of the enzyme, albeit weak; however, the relative I50 values suggested information about the active site. Antileukemic activity in L1210 lymphoid leukemia indicated no significant activity by these alpha-hydroxythiol esters.
A series of substituted guanidine derivatives were prepared and evaluated as potent and selective inhibitors of mitochondrial F(1)F(0) ATP hydrolase. The initial thiourethane derived lead molecules ...possessed intriguing in vitro pharmacological profiles, though contained moieties considered non-drug-like. Analogue synthesis efforts led to compounds with maintained potency and superior physical properties. Small molecules in this series which potently and selectivity inhibit ATP hydrolase and not ATP synthase may have utility as cardioprotective agents.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
