SAR about the B-ring of
N
2-aroyl anthranilamide
3e is described. B-ring
o-aminoalkylethers and B-ring
p-amine probes of the S1′ and S4 sites, respectively, afforded picomolar factor Xa and nanomolar ...factor IIa inhibitors that were potent in in vitro anticoagulation assays.
SAR about the B-ring of a series of
N
2-aroyl anthranilamide factor Xa (fXa) inhibitors is described. B-ring
o-aminoalkylether and B-ring
p-amine probes of the S1′ and S4 sites, respectively, afforded picomolar fXa inhibitors that performed well in in vitro anticoagulation assays.
The ketomethylene phenylalanal and alanal analogues of Cbz-Val-Phe-H and Cbz-Val-Ala-H have been prepared and the K
i values versus chicken gizzard smooth muscle calpain were determined. The ...ketomethylene isosteres were significantly less potent than the corresponding dipeptide aldehydes, and this loss in activity is attributed to the absence of a critical interaction between the P1–P2 amide bond and the peptide binding region of calpain.
The ketomethylene phenylalanal and alanal analogues of Cbz-Val-Phe-H and Cbz-Val-Ala-H have been prepared from α-methylene-γ-butyrolactone
4. The subsequent arylation, reduction, and bis-Swern oxidation generated the targeted γ-ketoaldehyde
9.
Background: Increased intake of whole-grain foods has been related to a reduced risk of developing diabetes and heart disease. One underlying pathway for this relation may be increased insulin ...sensitivity. Objective: We assessed the relation between dietary intake of whole grain-containing foods and insulin sensitivity (SI). Design: We evaluated data from the Insulin Resistance Atherosclerosis Study (IRAS Exam I, 1992-1994). Usual dietary intakes in 978 middle-aged adults with normal (67%) or impaired (33%) glucose tolerance were ascertained by using an interviewer-administered, validated food-frequency questionnaire. Whole-grain intake (servings per day) was derived from dark breads and high-fiber and cooked cereals. SI was assessed by minimal model analyses of the frequently sampled intravenous-glucose-tolerance test. Fasting insulin was measured by using a radioimmunoassay. We modeled the relation of whole-grain intake to log(SI + 1) and to log(insulin) by using multivariable linear regression. Results: On average, IRAS participants consumed 0.8 servings of whole grains/d. Whole-grain intake was significantly associated with SI (beta = 0.082, P = 0.0005) and insulin (beta = -0.0646, P = 0.019) after adjustment for demographics, total energy intake and expenditure, smoking, and family history of diabetes. The addition of body mass index and waist circumference attenuated but did not explain the association with SI. The addition of fiber and magnesium resulted in a nonsignificant association that is consistent with the hypothesis that these constituents account for some of the effect of whole grains on SI. Conclusion: Higher intakes of whole grains were associated with increases in insulin sensitivity.
The synthesis of 1-(5-hydroxy-4-(phenylmethyl)-3-oxazolidinyl)carbonyl-2-ethylpropylcarbamic acid phenylmethyl ester (
2; MDL 104,903), a potent inhibitor of calpain, is described. Synthesis of ...related compounds, which offer insights into the mechanism of action for
2, are also described, as is an O-acetyl prodrug derivative of
2.
This report describes the synthesis and biological evaluation of a novel hydroxyoxazolidine calpain inhibitor, MDL 104,903 (
2). Additional compounds designed to probe the mechanism of inactivation were prepared, as were compounds with additional conformational constraints. An O-acetyl prodrug of
2 (20a) was shown to convert to
2 in human plasma.
is among the top causes of bacterial endophthalmitis, an infectious disease of the intraocular fluids. The mechanisms by which
grows and thrives in the intraocular cavity are not well understood. We ...used a bacterial genome-wide assessment tool (transposon insertion site sequencing) to determine genes essential for
growth in vitreous humor. The results indicated that an ascorbic acid (AA) transport system subunit was important for growth. We created an isogenic gene deletion mutant of the AA transcriptional activator,
, in 2 strains of
. Growth curve analysis indicated that
deletion caused attenuated growth in vitro for both strains. However, in vivo vitreous humor infection in rabbits with either strain determined that
was necessary for growth in one strain but not the other. These results demonstrate that
may be important for fitness during
endophthalmitis depending on the background of the strain.
Valylprolyvalyl pentafluoroethyl ketones with different N-protecting groups were evaluated in vitro and in vivo as inhibitors of human neutrophil elastase (HNE). Several of these compounds were found ...to be orally active in HNE-induced rat and hamster lung hemorrhage models. The compound with 4-(4-morpholinylcarbonyl)benzoyl as the protecting group, 71 (MDL 101,146), was studied in greater detail. Hydration and epimerization studies were performed on 71 and related compounds in various media, including human blood serum. High-performance liquid chromatography studies on a reversed-phase system as a measure of the lipophilicity of 71 and related compounds revealed a small range of relative retention times wherein the orally active compounds fell. The Ki value determined for 71 vs HNE was 25 nM.
Androstenes bearing a cyclopropyl group attached to the C-17β position with a heteroatom linker, designed as mechanism-based inhibitors of steroid C
17(20) lyase, were found to be potent, ...time-dependent inhibitors of this enzyme.
Androstenes bearing a cyclopropyl group attached to the C-17β position with a heteroatom linker, of which
4 is a representative example, were designed as mechanism-based inhibitors of steroid C
)17(20 lyase, and were found to be potent, time-dependent inhibitors of this enzyme.
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