Species comparison of compounds with known blood pressure effects in a vascular smooth muscle cell collagen contraction assay.

Introduction: There is a great need for new approaches early in drug discovery that have the potential to improve clinical translation of compound-mediated cardiovascular effects. Current approaches frequently rely on in vivo animal models or in vitro tissue bath preparations, both of which are low throughput and costly. An in vitro surrogate screen for blood pressure using primary human cells may serve as a higher throughput method to quickly select compounds void of this secondary pharmacology and potentially improve late-stage drug development outcomes.

Performance of Spherical Quantum Well Down Converters in Solid State Lighting.

We report the color conversion performance of amber and red emitting quantum dots (QDs) on InGaN solid-state lighting (SSL) light emitting diode (LED) packages. Spherical quantum well (SQW) architectures (CdS/CdSeS/CdS) were prepared using a library of thio- and selenourea synthesis reagents and high throughput synthesis robotics. CdS/CdSeS QDs with narrow luminescence bands were coated with thick CdS shells (thickness = 1.

Drug-induced QT prolongation: Concordance of preclinical anesthetized canine model in relation to published clinical observations for ten CiPA drugs.

Introduction: The Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative differentiates torsadogenic risk of 28 drugs affecting ventricular repolarization based on multiple in vitro human derived ionic currents. However, a standardized prospective assessment of the electrophysiologic effects of these drugs in an integrated in vivo preclinical cardiovascular model is lacking. This study questioned whether QTc interval prolongation in a preclinical in vivo model could detect clinically reported QTc prolongation and assign torsadogenic risk for ten CiPA drugs.

Highly efficient capillary columns packed with superficially porous particles via sequential column packing.

Highly efficient capillary columns packed with superficially porous particles were created for use in ultrahigh pressure liquid chromatography. Superficially porous particles around 1.5μm in diameter were packed into fused silica capillary columns with 30, 50, and 75μm internal diameters.

What do hotels and hospitals have in common? How we can learn from the hotel industry to take better care of patients.

Despite widely divergent public perceptions and goals, hotels and hospitals share many core characteristics. Both serve demanding and increasingly well-informed clienteles, both employ a large hierarchy of workers with varying levels of responsibility, and both have payments that are increasingly tied to customer/patient evaluations. In the hotel industry, decades of management experience and market research have led to widespread improvements and innovations that improve customer satisfaction.

The design and synthesis of a potent glucagon receptor antagonist with favorable physicochemical and pharmacokinetic properties as a candidate for the treatment of type 2 diabetes mellitus.

A novel and potent small molecule glucagon receptor antagonist for the treatment of diabetes mellitus is reported. This candidate, (S)-3-[4-(1-{3,5-dimethyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenoxy}butyl)benzamido]propanoic acid, has lower molecular weight and lipophilicity than historical glucagon receptor antagonists, resulting in excellent selectivity in broad-panel screening, lower cytotoxicity, and excellent overall in vivo safety in early pre-clinical testing. Additionally, it displays low in vivo clearance and excellent oral bioavailability in both rats and dogs.

The cultural construction of self and well-being: a tale of two cities.

Does local context (e.g., city of residence) matter for self and well-being? We theorized that it does because local contexts diverge in prevalent historically-derived ideas, norms, and products.

In vivo imaging of endogenous pancreatic β-cell mass in healthy and type 1 diabetic subjects using 18F-fluoropropyl-dihydrotetrabenazine and PET.

Unlabelled: The ability to noninvasively measure endogenous pancreatic β-cell mass (BCM) would accelerate research on the pathophysiology of diabetes and revolutionize the preclinical development of new treatments, the clinical assessment of therapeutic efficacy, and the early diagnosis and subsequent monitoring of disease progression. The vesicular monoamine transporter type 2 (VMAT2) is coexpressed with insulin in β-cells and represents a promising target for BCM imaging.

Methods: We evaluated the VMAT2 radiotracer (18)F-fluoropropyl-dihydrotetrabenazine ((18)F-FP-(+)-DTBZ, also known as (18)F-AV-133) for quantitative PET of BCM in healthy control subjects and patients with type 1 diabetes mellitus.

Discovery of (S)-6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic acid as a hepatoselective glucokinase activator clinical candidate for treating type 2 diabetes mellitus.

Glucokinase is a key regulator of glucose homeostasis, and small molecule allosteric activators of this enzyme represent a promising opportunity for the treatment of type 2 diabetes. Systemically acting glucokinase activators (liver and pancreas) have been reported to be efficacious but in many cases present hypoglycaemia risk due to activation of the enzyme at low glucose levels in the pancreas, leading to inappropriately excessive insulin secretion. It was therefore postulated that a liver selective activator may offer effective glycemic control with reduced hypoglycemia risk.

Modeling the mechanism of action of a DGAT1 inhibitor using a causal reasoning platform.

Triglyceride accumulation is associated with obesity and type 2 diabetes. Genetic disruption of diacylglycerol acyltransferase 1 (DGAT1), which catalyzes the final reaction of triglyceride synthesis, confers dramatic resistance to high-fat diet induced obesity. Hence, DGAT1 is considered a potential therapeutic target for treating obesity and related metabolic disorders.

Islet-selectivity of G-protein coupled receptor ligands evaluated for PET imaging of pancreatic β-cell mass.

A critical unmet need exists for methods to quantitatively measure endogenous pancreatic β-cell mass (BCM) for the clinical evaluation of therapies to prevent or reverse loss of BCM and diabetes progression. Our objective was to identify G-protein coupled receptors (GPCRs) that are expressed with a high degree of specificity to islet β-cells for receptor-targeted imaging of BCM. GPCRs enriched in pancreatic islets relative to pancreas acinar and hepatic tissue were identified using a database screen.

Defective glycogenesis contributes toward the inability to suppress hepatic glucose production in response to hyperglycemia and hyperinsulinemia in zucker diabetic fatty rats.

Objective: Examine whether normalizing net hepatic glycogenesis restores endogenous glucose production and hepatic glucose phosphorylation in response to diabetic levels of plasma glucose and insulin in Zucker diabetic fatty rats (ZDF).

Research Design And Methods: Hepatic glucose and intermediate fluxes (µmol · kg(-1) · min(-1)) were measured with and without a glycogen phosphorylase inhibitor (GPI) using [2-(3)H]glucose, [3-(3)H]glucose, and [U-(14)C]alanine in 20 h-fasted conscious ZDF and their lean littermates (ZCL) under clamp conditions designed to maintain diabetic levels of plasma glucose and insulin.

Results: With infusion of GPI into ZDF (ZDF-GPI+G), compared with vehicle infused ZDF (ZDF-V), high glycogen phosphorylase a activity was decreased and low synthase I activity was increased to that of ZCL.

Polyomic profiling reveals significant hepatic metabolic alterations in glucagon-receptor (GCGR) knockout mice: implications on anti-glucagon therapies for diabetes.

Background: Glucagon is an important hormone in the regulation of glucose homeostasis, particularly in the maintenance of euglycemia and prevention of hypoglycemia. In type 2 Diabetes Mellitus (T2DM), glucagon levels are elevated in both the fasted and postprandial states, which contributes to inappropriate hyperglycemia through excessive hepatic glucose production. Efforts to discover and evaluate glucagon receptor antagonists for the treatment of T2DM have been ongoing for approximately two decades, with the challenge being to identify an agent with appropriate pharmaceutical properties and efficacy relative to potential side effects.

Impact of a glycogen phosphorylase inhibitor and metformin on basal and glucagon-stimulated hepatic glucose flux in conscious dogs.

The effects of a glycogen phosphorylase inhibitor (GPI) and metformin (MT) on hepatic glucose fluxes (μmol · kg(-1) · min(-1)) in the presence of basal and 4-fold basal levels of plasma glucagon were investigated in 18-h fasted conscious dogs. Compared with the vehicle treatment, GPI infusion suppressed net hepatic glucose output (NHGO) completely (-3.8 ± 1.

1-((3S,4S)-4-amino-1-(4-substituted-1,3,5-triazin-2-yl) pyrrolidin-3-yl)-5,5-difluoropiperidin-2-one inhibitors of DPP-4 for the treatment of type 2 diabetes.

A 3-amino-4-substituted pyrrolidine series of dipeptidyl peptidase IV (DPP-4) inhibitors was rapidly developed into a candidate series by identification of a polar valerolactam replacement for the lipophilic 2,4,5-trifluorophenyl pharmacophore. The addition of a gem-difluoro substituent to the lactam improved overall DPP-4 inhibition and an efficient asymmetric route to 3,4-diaminopyrrolidines was developed. Advanced profiling of a subset of analogs identified 5o with an acceptable human DPP-4 inhibition profile based on a rat PK/PD model and a projected human dose that was suitable for clinical development.

Enhanced fluidity liquid chromatography for hydrophilic interaction separation of nucleosides.

The application of enhanced fluidity liquid (EFL) mobile phases to improving isocratic chromatographic separation of nucleosides in hydrophilic interaction liquid chromatography (HILIC) mode is described. The EFL mobile phase was created by adding carbon dioxide to a methanol/buffer solution. Previous work has shown that EFL mobile phases typically increase the efficiency and the speed of the separation.

The application of target information and preclinical pharmacokinetic/pharmacodynamic modeling in predicting clinical doses of a Dickkopf-1 antibody for osteoporosis.

PF-04840082 is a humanized prototype anti-Dickkopf-1 (Dkk-1) immunoglobulin isotype G(2) (IgG(2)) antibody for the treatment of osteoporosis. In vitro, PF-04840082 binds to human, monkey, rat, and mouse Dkk-1 with high affinity. After administration of PF-04840082 to rat and monkey, free Dkk-1 concentrations decreased rapidly and returned to baseline in a dose-dependent manner.

Piperidinyl-2-phenethylamino inhibitors of DPP-IV for the treatment of type 2 diabetes.

A highly ligand efficient lead molecule was rapidly developed into a DPP-IV selective candidate series using focused small library synthesis. A significant hurdle for series advancement was genetic safety since some agents in this series impaired chromosome division that was detected using the in vitro micronucleus assay. A recently developed high-throughput imaging-based in vitro micronucleus assay enabled the identification of chemical space with a low probability of micronucleus activity.

(3,3-Difluoro-pyrrolidin-1-yl)-[(2S,4S)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone: a potent, selective, orally active dipeptidyl peptidase IV inhibitor.

A series of 4-substituted proline amides was synthesized and evaluated as inhibitors of dipeptidyl pepdidase IV for the treatment of type 2 diabetes. (3,3-Difluoro-pyrrolidin-1-yl)-[(2S,4S)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone (5) emerged as a potent (IC(50) = 13 nM) and selective compound, with high oral bioavailability in preclinical species and low plasma protein binding. Compound 5, PF-00734200, was selected for development as a potential new treatment for type 2 diabetes.

The hepatic PP1 glycogen-targeting subunit interaction with phosphorylase a can be blocked by C-terminal tyrosine deletion or an indole drug.

The inhibition of hepatic glycogen-associated protein phosphatase-1 (PP1-G(L)) by glycogen phosphorylase a prevents the dephosphorylation and activation of glycogen synthase, suppressing glycogen synthesis when glycogenolysis is activated. Here, we show that a peptide ((280)LGPYY(284)) comprising the last five amino acids of G(L) retains high-affinity interaction with phosphorylase a and that the two tyrosines play crucial roles. Tyr284 deletion abolishes binding of phosphorylase a to G(L) and replacement by phenylalanine is insufficient to restore high-affinity binding.

(3R,4S)-4-(2,4,5-Trifluorophenyl)-pyrrolidin-3-ylamine inhibitors of dipeptidyl peptidase IV: synthesis, in vitro, in vivo, and X-ray crystallographic characterization.

A series of pyrrolidine based inhibitors of dipeptidyl peptidase IV were developed from a high throughput screening hit for the treatment of type 2 diabetes. Potency, selectivity, and pharmacokinetic properties were optimized resulting in the identification of a pre-clinical candidate for further profiling.

Astrocyte glycogen sustains neuronal activity during hypoglycemia: studies with the glycogen phosphorylase inhibitor CP-316,819 ([R-R*,S*]-5-chloro-N-[2-hydroxy-3-(methoxymethylamino)-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide).

Glycogen in the brain is localized almost exclusively to astrocytes. The physiological function of this energy store has been difficult to establish because of the difficulty in manipulating brain glycogen concentrations in vivo. Here, we used a novel glycogen phosphorylase inhibitor, CP-316,819 ([R-R*,S*]-5-chloro-N-[2-hydroxy-3-(methoxymethylamino)-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide), that causes glycogen accumulation under normoglycemic conditions but permits glycogen utilization when glucose concentrations are low.

Three-dimensional quantitative structure-activity relationship analysis of human CYP51 inhibitors.

CYP51 fulfills an essential requirement for all cells, by catalyzing three sequential mono-oxidations within the cholesterol biosynthesis cascade. Inhibition of fungal CYP51 is used as a therapy for treating fungal infections, whereas inhibition of human CYP51 has been considered as a pharmacological approach to treat dyslipidemia and some forms of cancer. To predict the interaction of inhibitors with the active site of human CYP51, a three-dimensional quantitative structure-activity relationship model was constructed.