The identification of several potent pyrazole-based inhibitors of bacterial dihydroorotate dehydrogenase (DHODase) via a directed parallel synthetic approach is described below. The initial ...pyrazole-containing lead compounds were optimized for potency against Helicobacter pylori DHODase. Using three successive focused libraries, inhibitors were rapidly identified with the following characteristics: K(i) < 10 nM against H. pylori DHODase, sub-microg/mL H. pylori minimum inhibitory concentration activity, low molecular weight, and >10 000-fold selectivity over human DHODase.
Benzothiazole benzimidazole (
S)-isothiazolidinone ((
S)-IZD) derivatives
5 were discovered through a peptidomimetic modification of the tripeptide (
S)-IZD protein tyrosine phosphatase 1B (PTP1B) ...inhibitor
1. These derivatives are potent, competitive, and reversible inhibitors of PTP1B with improved caco-2 permeability. An X-ray co-crystal structure of inhibitor
5/PTP1B at 2.2
Å resolution demonstrated that the benzothiazole benzimidazole forms bi-dentate H-bonds to Asp48, and the benzothiazole interacts with the surface of the protein in a solvent exposed region towards the C-site. The design, synthesis, and SAR of this novel series of benzothiazole benzimidazole containing (
S)-IZD inhibitors of PTP1B are presented herein.
To evaluate the effect of ruboxistaurin, an orally administered protein kinase C beta (PKC beta) isozyme-selective inhibitor, on vision loss in patients with diabetes.
Thirty-six-month, randomized, ...double-masked, placebo-controlled, parallel, multicenter trial.
Six hundred eighty-five patients randomized at 70 clinical sites.
Ophthalmologic examination was performed at screening and at each 3-month visit. Retinopathy status was assessed every 6 months with Early Treatment Diabetic Retinopathy Study (ETDRS) standard 7-field 30 degrees color stereoscopic fundus photography. Levels of diabetic retinopathy and diabetic macular edema were determined by 2 independent graders masked to site and treatment assignment, with additional independent adjudication as required. Eligible patients had a best-corrected visual acuity (VA) score of > or =45 letters, retinopathy level > or = 47A and < or = 53E, and no prior panretinal photocoagulation in at least one eye.
Effect of oral ruboxistaurin (32 mg/day) on reduction of sustained moderate visual loss (> or =15-letter decrease in ETDRS VA score maintained > or = 6 months) in patients with moderately severe to very severe nonproliferative diabetic retinopathy.
Sustained moderate visual loss occurred in 9.1% of placebo-treated patients versus 5.5% of ruboxistaurin-treated patients (40% risk reduction, P = 0.034). Mean VA was better in the ruboxistaurin-treated patients after 12 months. Baseline-to-end point visual improvement of > or =15 letters was more frequent (4.9% vs. 2.4%) and > or =15-letter worsening was less frequent (6.7% vs. 9.9%) in ruboxistaurin-treated patients relative to placebo (P = 0.005). When clinically significant macular edema was >100 microm from the center of the macula at baseline, ruboxistaurin treatment was associated with less frequent progression of edema to within 100 microm (68% vs. 50%, P = 0.003). Initial laser treatment for macular edema was 26% less frequent in eyes of ruboxistaurin-treated patients (P = 0.008).
Oral ruboxistaurin treatment reduced vision loss, need for laser treatment, and macular edema progression, while increasing occurrence of visual improvement in patients with nonproliferative retinopathy.
The structure-based design and discovery of the isothiazolidinone (IZD) heterocycle as a mimic of phosphotyrosine (pTyr) has led to the identification of novel IZD-containing inhibitors of protein ...tyrosine phosphatase 1B (PTP1B). The structure–activity relationships (SARs) of peptidic IZD-containing inhibitors of PTP1B are described along with a novel synthesis of the aryl-IZD fragments via a Suzuki coupling. The SAR revealed the saturated IZD heterocycle (
42) is the most potent heterocyclic pTyr mimetic compared to the unsaturated IZD (
25), the thiadiazolidinone (TDZ) (
38), and the regioisomeric unsaturated IZD (
31). The X-ray crystal structures of
11c and
25 complexed with PTP1B were solved and revealed nearly identical binding interactions in the active site. Ab initio calculations effectively explain the strong binding of the (
S)-IZD due to the preorganized binding of the IZD in its low energy conformation.
A case is presented of a primigravida with transient diabetes insipidus, gestational hypertension, and multiple seizures resistant to magnesium sulfate and diazepam. After addition of phenytoin, no ...further seizures occurred. Transient diabetes insipidus in pregnancy has been previously associated with hypertension, liver dysfunction, and fetal distress. Considered with previous cases, it is suggested that seizures may frequently be part of this syndrome.
Background & Aims: The APC tumor suppressor is well known for its ability to regulate Wnt signaling through mediation of β-catenin levels in the cell. Transient over expression of the tumor ...suppressor gene APC in colon cancer cells prevents entry into S phase of the cell cycle, a phenotype only partially restored by cotransfection of a transcriptionally active form of β-catenin. In an attempt to define its transcription-independent tumor suppressor functions, we tested whether APC directly affects DNA replication. Methods: A transcriptionally quiescent in vitro DNA replication system, the polymerase chain reaction, DNA binding assays, and transient transfections in colon cancer cell lines were used to determine the effects of APC on DNA replication and the mechanism by which it works. Results: We report that exogenous full-length APC inhibits replication of template DNA through a function that maps to amino acids 2140–2421, a region of the protein commonly lost by somatic or germline mutation. This segment of APC directly interacts with DNA, while mutation of the DNA-binding S(T)PXX motifs within it abolishes DNA binding and reduces inhibition of DNA replication. Phosphorylation of this segment by cyclin-dependent kinases also reduces inhibition of DNA replication. Furthermore, transient transfection of an APC segment encoding amino acids 2140–2421 into a colon cancer cell line with mutant APC prevents cell cycle progression into or through S phase. Conclusions: Our results suggest that APC can negatively regulate cell cycle progression through inhibition of DNA replication by direct interaction with DNA.
We report the discovery of a class of pyrazole-based compounds that are potent inhibitors of the dihydroorotate dehydrogenase of Helicobacter pylori but that do not inhibit the cognate enzymes from ...Gram-positive bacteria or humans. In culture these compounds inhibit the growth of H. pylori selectively, showing no effect on other Gram-negative or Gram-positive bacteria or human cell lines. These compounds represent the first examples of H. pylori-specific antibacterial agents. Cellular activity within this structural class appears to be due to dihydroorotate dehydrogenase inhibition. Minor structural changes that abrogate in vitro inhibition of the enzyme likewise eliminate cellular activity. Furthermore, the minimum inhibitory concentrations of these compounds increase upon addition of orotate to the culture medium in a concentration-dependent manner, consistent with dihydroorotate dehydrogenase inhibition as the mechanism of cellular inhibition. The data presented here suggest that targeted inhibition of de novo pyrimidine biosynthesis may be a valuable mechanism for the development of antimicrobial agents selective for H. pylori.
Pyrido3,2-bpyrazin-3(4H)-ones and pteridin-7(8H)-ones were evaluated as corticotropin-releasing factor-1 receptor antagonists. The synthesis, SAR studies and pharmacokinetic evaluation of these ...analogs are described herein.
Various types of infrared radiometers have been used to make measurements of surface temperature from aircraft and to make measurements of temperature during cloud traverses. Instruments for surface ...temperature are sensitive in the water-vapor window 8 to 13 μ and in the range from 8 to 35 μ, and instruments for cloud temperature are sensitive in the 15 μ CO2 band. The instrumentation shows great promise for operational measurement of surface temperature from aircraft. The infrared atmospheric thermometer (IRAT) (15 μ CO2 band) makes it possible to measure free-air and in-cloud temperatures remotely without actual exposure to the cloud droplets which cause errors in other types of sensors. Relative accuracy of the IRAT is ±0.25C.
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