Structure-based discovery of LpxC inhibitors.

The emergence and spread of multidrug-resistant (MDR) Gram negative bacteria presents a serious threat for public health. Novel antimicrobials that could overcome the resistance problems are urgently needed. UDP-3-O-(R-3-hydroxymyristol)-N-acetylglucosamine deacetylase (LpxC) is a cytosolic zinc-based deacetylase that catalyzes the first committed step in the biosynthesis of lipid A, which is essential for the survival of Gram-negative bacteria.

Discovery of indole inhibitors of chemokine receptor 9 (CCR9).

Irritable bowel diseases (IBD) such as Crohn's disease (CD) and ulcerative colitis (UC) are serious chronic diseases affecting millions of patients worldwide. Studies of human chemokine biology has suggested C-C chemokine receptor 9 (CCR9) may be a key mediator of pro-inflammatory signaling. Discovery of agents that inhibit CCR9 may lead to new therapies for CD and UC patients.

Biarylsulfonamide CCR9 inhibitors for inflammatory bowel disease.

Inflammatory bowel disease, including Crohn's disease and ulcerative colitis, affects millions of people worldwide. CCR9 has been shown to be a key chemokine receptor mediating the local inflammatory responses in the GI tract. The CCR9 inhibitor Vercirnon advanced to phase 3 clinical trials, but carries several liabilities which we sought to improve.

Immune cells control skin lymphatic electrolyte homeostasis and blood pressure.

The skin interstitium sequesters excess Na+ and Cl- in salt-sensitive hypertension. Mononuclear phagocyte system (MPS) cells are recruited to the skin, sense the hypertonic electrolyte accumulation in skin, and activate the tonicity-responsive enhancer-binding protein (TONEBP, also known as NFAT5) to initiate expression and secretion of VEGFC, which enhances electrolyte clearance via cutaneous lymph vessels and increases eNOS expression in blood vessels. It is unclear whether this local MPS response to osmotic stress is important to systemic blood pressure control.

Fractionating nanosilver: importance for determining toxicity to aquatic test organisms.

This investigation applied novel techniques for characterizing and fractionating nanosilver particles and aggregates and relating these measurements to toxicological endpoints. The acute toxicity of eight nanosilver suspensions of varying primary particle sizes (10-80 nm) and coatings (citrate, polyvinylpyrrolidone, EDTA, proprietary) was assessed using three aquatic test organisms (Daphnia magna, Pimephales promelas, Pseudokirchneriella subcapitata). When 48-h lethal median concentrations (LC50) were expressed as total silver, both D.

Two naturally occurring mutations in the type 1 melanin-concentrating hormone receptor abolish agonist-induced signaling.

The melanin-concentrating hormone (MCH) receptor type 1 (MCHR1) is a seven-transmembrane domain protein that modulates orexigenic activity of MCH, the corresponding endogenous peptide agonist. MCH antagonists are being explored as a potential treatment for obesity. In the current study, we examined the pharmacological impact of 11 naturally occurring mutations in the human MCHR1.

Mononuclear phagocyte system depletion blocks interstitial tonicity-responsive enhancer binding protein/vascular endothelial growth factor C expression and induces salt-sensitive hypertension in rats.

We showed recently that mononuclear phagocyte system (MPS) cells provide a buffering mechanism for salt-sensitive hypertension by driving interstitial lymphangiogenesis, modulating interstitial Na(+) clearance, and increasing endothelial NO synthase protein expression in response to very high dietary salt via a tonicity-responsive enhancer binding protein/vascular endothelial growth factor C regulatory mechanism. We now tested whether isotonic saline and deoxycorticosterone acetate (DOCA)-salt treatment leads to a similar regulatory response in Sprague-Dawley rats. Male rats were fed a low-salt diet and received tap water (low-salt diet LSD), 1.

Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism.

In salt-sensitive hypertension, the accumulation of Na(+) in tissue has been presumed to be accompanied by a commensurate retention of water to maintain the isotonicity of body fluids. We show here that a high-salt diet (HSD) in rats leads to interstitial hypertonic Na(+) accumulation in skin, resulting in increased density and hyperplasia of the lymphcapillary network. The mechanisms underlying these effects on lymphatics involve activation of tonicity-responsive enhancer binding protein (TonEBP) in mononuclear phagocyte system (MPS) cells infiltrating the interstitium of the skin.

Influence of nanotube preparation in aquatic bioassays.

Knowledge gaps in nanomaterial fate and toxicity currently limit the ability of risk assessments to characterize the environmental implications of nanomaterials. This problem is further complicated by the lack of standardized characterization and preparation methodologies for researchers to gain the needed information to assist risk assessors. In the present study, data were generated to determine if multiwalled nanotube (MWNT) fate and toxicity are altered by engineered surface modifications or by different dispersal methods.

Brønsted base catalysts.

Chiral organic Brønsted bases have emerged as highly efficient catalysts for enantioselective transformations. Since their early use in enantiomeric separation processes, chiral organic Brønsted base catalysis has advanced significantly to include both natural and designed catalysts. Insight into the mode of action of the organocatalysts has promoted modifications in catalyst structures to expand the application to numerous asymmetric reactions.

Enantioselective synthesis of SNAP-7941: chiral dihydropyrimidone inhibitor of MCH1-R.

An enantioselective synthesis of SNAP-7941, a potent melanin concentrating hormone receptor antagonist, was achieved by using two organocatalytic methods. The first method utilized to synthesize the enantioenriched dihydropyrimidone core was the Cinchona alkaloid-catalyzed Mannich reaction of beta-keto esters to acylimines and the second was the chiral phosphoric acid-catalyzed Biginelli reaction. Completion of the synthesis was accomplished via selective urea formation at the N3 position of the dihydropyrimidone with the 3-(4-phenylpiperidin-1-yl)propylamine side chain fragment.