DBPR108, a novel dipeptidyl peptidase-4 inhibitor with antihyperglycemic activity.

AIMS: Dipeptidyl peptidase 4 (DPP-4) is a valid molecular drug target from which its inhibitors have been developed as medicines for treating diabetes. The present study evaluated a new synthetic DPP-4-specific inhibitor of small molecule DBPR108 for pharmacology and pharmacokinetic profiles. MAIN METHODS: DBPR108 of various doses was orally administered to rats, diabetic mice, and dogs and the systemic circulating DPP-4 activities in the animals were measured to demonstrate the pharmacological mechanisms of action via DPP-4 inhibition. Upon an oral administration of DBPR108, the serum active GLP-1 and insulin levels of the rats challenged with an oral glucose ingestion were measured. Oral glucose tolerance test in diet-induced obese mice was performed to examine if DBPR108 increases the glucose tolerability in animals. KEY FINDINGS: Orally administered DBPR108 inhibited the systemic plasma DPP-4 activities in rats, dogs and diabetic mice in a dose-dependent manner. DBPR108 caused elevated serum levels of active GLP-1 and insulin in the rats. DBPR108 dose-dependently increased the glucose tolerability in diet-induced obese (DIO) mice and, furthermore, DIO mice treated with DBPR108 (0.1 mg/kg) in combination with metformin (50 or 100 mg/kg) showed a prominently strong increase in the glucose tolerability. SIGNIFICANCE: DBPR108 is a novel DPP-4-selective inhibitor of small molecule that demonstrated potent in vivo pharmacological effects and good safety profiles in animals. DBPR108 is now a drug candidate being further developed in the clinical studies as therapeutics for treating diabetes.

Evaluation of tert-butyl isosteres: case studies of physicochemical and pharmacokinetic properties, efficacies, and activities.

The tert-butyl group is a common motif in medicinal chemistry. Its incorporation into bioactive compounds is often accompanied by unwanted property modulation, such as increased lipophilicity and decreased metabolic stability. Several alternative substituents are available for the drug discovery process. Herein, physicochemical data of two series of drug analogues of bosentan and vercirnon are documented as part of a comparative study of tert-butyl, pentafluorosulfanyl, trifluoromethyl, bicyclo[1.1.1]pentanyl, and cyclopropyl-trifluoromethyl substituents.

The somatostatin receptor 4 agonist J-2156 reduces mechanosensitivity of peripheral nerve afferents and spinal neurons in an inflammatory pain model.

Somatostatin (SST) is a peptide hormone that regulates the endocrine system and affects neurotransmission via interaction with G protein-coupled SST receptors and inhibition of the release of different hormones. The aim of this study was to investigate whether the analgesic properties of the selective SSTR4 agonist J-2156 are mediated via peripheral and/or spinal receptors. Effect on mechanical hyperalgesia in the Complete Freund׳s Adjuvant (CFA) model was measured after intraperitoneal application of J-2156. Electrophysiological neuronal recordings were conducted 24 h after injection of CFA or vehicle into the paw of Wistar rats. Mechanosensitivity of peripheral afferents of the saphenous nerve as well as of spinal wide dynamic range (WDR) and nociceptive-specific (NS) neurons were measured after systemic or spinal application of J-2156. In CFA animals J-2156 dose dependently reduced hyperalgesia in behavioral studies. The minimal effective dose was 0.1 mg/kg. Mechanosensitivity of peripheral afferents and spinal neurons was significantly reduced by J-2156. NS neurons were dose dependently inhibited by J-2156 while in WDR neurons only the highest concentration of 100 µM had an effect. In sham controls, J-2156 had no effect on neuronal activity. We demonstrated that J-2156 dose-dependently reduces peripheral and spinal neuronal excitability in the CFA rat model without affecting physiological pain transmission. Given the high concentration of the compound required to inhibit spinal neurons, it is unlikely that the behavioral effect seen in CFA model is mediated centrally. Overall these data demonstrated that the analgesic effect of J-2156 is mediated mainly via peripheral SST4 receptors.

Fragrance material review on 1,3-dimethyl-3-phenylbutyl acetate.

A toxicologic and dermatologic review of 1,3-dimethyl-3-phenylbutyl acetate when used as a fragrance ingredient is presented. 1,3-Dimethyl-3-phenylbutyl acetate is a member of the fragrance structural group Aryl Alkyl Alcohol Simple Acid Esters (AAASAE). The AAASAE fragrance ingredients are prepared by reacting an aryl alkyl alcohol with a simple carboxylic acid (a chain of 1 to 4 carbons) to generate formate, acetate, propionate, butyrate, isobutyrate and carbonate esters. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for 1,3-dimethyl-3-phenylbutyl acetate were evaluated, then summarized, and includes: physical properties, acute toxicity, skin irritation, mucous membrane (eye) irritation, skin sensitization, elicitation, phototoxicity, and photoallergy data. A safety assessment of the entire AAASAE will be published simultaneously with this document. Please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all AAASAE in fragrances.

Two cases of acute propane/butane poisoning in prison.

Hydrocarbon inhalation is seldom chosen as a means to commit suicide. This practice is exclusively a prerogative of the prison population; it is, however, only exceptionally found in this environment. The two cases of lethal inhalation of propane/butane gas observed by us over a very short time occurred in this context. Toxicologic analyses were performed by means of gas chromatography (head space) and revealed a propane/butane mixture in all specimens (heart blood, bile, and urine) except vitreous humor. Although fatal arrhythmia posthydrocarbon gas abuse is well known, the concentrations of the two hydrocarbons were sufficient to induce death by asphyxiation and were distributed (fairly) homogeneously in all biological fluids and organs examined, a parameter permitting one to assume that death occurred within a relatively short period of time. The absence of finding in vitreous humor and the trace amount in urine suggests that both men died very quickly.

Partition of bispyridinium oximes (trimedoxime and K074) administered in therapeutic doses into different parts of the rat brain.

The penetration of acetylcholinesterase reactivators (oximes) into the central nervous system is typically restricted by the blood-brain barrier. Although oximes are highly hydrophilic compounds, some contradictory results confirming permeation into the brain exist. The aim of this study is to verify the penetration of oximes through the blood-brain barrier and to detect their levels achieved in different brain regions 60 min after the administration. It was confirmed that oximes are able to penetrate into the brain after injection of therapeutic doses corresponding with 5% of LD(50). The level in whole brain was 0.58% for trimedoxime and 0.85% for the experimental drug oxime K074 as the percentage of their plasma concentration. The highest concentration was found in frontal cortex (trimedoxime 2.27%; oxime K074 0.95%) and lowest in basal ganglia (trimedoxime 0.86%; oxime K074 0.42%). Entry of oximes into the brain is minimal, but some low reactivation effect should be expected. The reactivation potency of oximes might be higher or lower, depending on the real oxime concentration in a given area.

A 13-week nose-only inhalation toxicity study for perfluoro-n-butyl iodide (PFBI) in rats with recommended occupational exposure levels.

A 13-week study was conducted to develop occupational exposure limits (OELs) for the solvent perfluoro-n-butyl iodide (PFBI). Fischer 344 rats (15 males & 10 females per group) were exposed for 6 h/day to 0 (air control), 500, 1500, or 5000 ppm PFBI vapor for 5 days/week for 13 consecutive weeks (at least 65 exposures) followed by a 4-week recovery period. Clinical observations, body weights, clinical pathology, organ weights, and histopathology as well as detailed evaluations of neurotoxicity and thyroid function parameters were conducted at the end of the treatment period for up to 10 animals/sex/group with 5 males/group held for a 4-week recovery period. Findings in the thyroid target tissue consisted of a minimal thyroid follicular cell hypertrophy occasionally accompanied by hyperplasia, but without an increase in thyroid weight in the 500, 1500, and 5000 ppm males. At > or = 500 ppm, there was also increased thyroid stimulating hormone in females and increased T(3) and T(4) in animals of both sexes. These effects resolved following a 4-week recovery period in the males evaluated. Minor clinical pathology variations in all PFBI exposure groups were not considered biologically significant. A 9.4% reduction in absolute body weight in the 5000 ppm males was observed. Dosimetric adjustments for daily exposure time and uncertainty factors were selected to provide a basis for the proposed OELs. For acute (single event) exposures, a ceiling OEL of 3900 ppm, and for repeated exposures, an 8-h time-weighted average of 40 ppm PFBI were proposed.

Molecular dynamics and partitioning of di-tert-butyl nitroxide in stratum corneum membranes: effect of terpenes.

In this work, we have used electron paramagnetic resonance (EPR) spectroscopy of the small spin label di-tert-butyl nitroxide (DTBN), which partitions the aqueous and hydrocarbon phases, to study the interaction of the terpenes alpha-terpineol, 1,8-cineole, L(-)-carvone and (+)-limonene with the uppermost skin layer, the stratum corneum, and the membrane models of 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) and 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC). The EPR spectra indicated that the terpenes increase both the partition coefficient and the rotational correlation time of the spin labels in the stratum corneum membranes, whereas similar effects were observed in the DMPC and DPPC bilayers only at temperatures below the liquid-crystalline phase. The EPR parameter associated to probe polarity inside the membranes showed thermotropically induced changes, suggesting relocations of spin probe, which were dependent on the membrane phases. While the DMPC and DPPC bilayers showed abrupt changes in the partitioning and rotational correlation time parameters in the phase transitions, the SC membranes were characterized by slight changes in the total range of measured temperatures, presenting the greatest changes or membranes reorganizations in the temperature range of approximately 50 to approximately 74 degrees C. The results suggest that terpenes act as spacers, weakening the hydrogen-bonded network at the polar interface and thus fluidizing the stratum corneum lipids.

1-Amido-1-phenyl-3-piperidinylbutanes--CCR5 antagonists for the treatment of HIV: part 2.

Optimisation of a series of 4-piperidinyltriazoles led to the identification of compound 28a which showed good whole cell antiviral activity, excellent selectivity over the hERG ion channel and complete oral absorption.

[Isobutane driven salbutamol sulfate metered dose inhaler: formulation selection and respiratory tract absorption in guinea pigs].

This paper is to study the iso-butane (A-31)-driven salbutamol sulfate (SS) metered dose inhaler (MDI) formulations and inhaling status in guinea pigs. Solubility determination and orthogonal design were used to screen non-chlorofluorocarbon (CFC) SS MDI formulations. Intubation inhalation of MDI in guinea pigs was used as a main administration method. Fluorescence HPLC detection method was testified as a potential method in assaying the concentration of SS in plasma of guinea pigs after inhaling various SS MDI formulations. Analysis of the data was executed with statistical moment calculation from which pharmacokinetic parameters were obtained. The results show that A-31 based on SS MDI formulations were screened and the guinea pigs in vivo determination method after inhaling SS MDI was established. The zero-moment rations of SS/A-31 MDI formulation to contrast sample and CFC SS MDI was 143.26% and 147.01%, respectively. The first moment value of SS/A-31 MDI formulation was the highest. It is a preliminary conclusion that the absorption result of SS/A-31 MDI formulation inhaled by guinea pigs is equivalent to HFA-134a formulation in sale and better than CFC formulation. A-31 could be used as a potential substitute candidate for CFC MDI propellant.

Fragrance material review on 1,3-dimethyl-3-butenyl salicylate.

A toxicologic and dermatologic review of 1,3-dimethyl-3-butenyl salicylate when used as a fragrance ingredient is presented.

Fragrance material review on 4-(1,2-epoxy-2,6,6-trimethylcyclohexyl)-3-buten-2-one.

A toxicologic and dermatologic review of 4-(1,2-epoxy-2,6,6-trimethylcyclohexyl)-3-buten-2-one when used as a fragrance ingredient is presented.

Fragrance material review on 4-(3,5,6-trimethyl-3-cyclohexen-1-yl)-3-buten-2-one.

A toxicologic and dermatologic review of 4-(3,5,6-trimethyl-3-cyclohexen-1-yl)-3-buten-2-one when used as a fragrance ingredient is presented.

Fragrance material review on 3-methyl-4-(2,4,6-trimethyl-3-cyclohexen-1-yl)-3-buten-2-one.

A toxicologic and dermatologic review of 3-methyl-4-(2,4,6-trimethyl-3-cyclohexen-1-yl)-3-buten-2-one when used as a fragrance ingredient is presented.

Fragrance material review on 3-methyl-2-butenyl salicylate.

A toxicologic and dermatologic review of 3-methyl-2-butenyl salicylate when used as a fragrance ingredient is presented.

Fragrance material review on 4-(2,4,6-trimethyl-3-cyclohexen-1-yl)-3-buten-2-one.

A toxicologic and dermatologic review of 4-(2,4,6-trimethyl-3-cyclohexen-1-yl)-3-buten-2-one when used as a fragrance ingredient is presented.

In vitro metabolism of (nitrooxy)butyl ester nitric oxide-releasing compounds: comparison with glyceryl trinitrate.

We investigated the in vitro metabolism of two (nitrooxy)butyl ester nitric oxide (NO) donor derivatives of flurbiprofen and ferulic acid, [1,1'-biphenyl]-4-acetic acid-2-fluoro-alpha-methyl-4-(nitrooxy)butyl ester (HCT 1026) and 3-(4-hydroxy-3-methoxyphenyl)-2-propenoic acid 4-(nitrooxy)butyl ester (NCX 2057), respectively, in rat blood plasma and liver subcellular fractions compared with (nitrooxy)butyl alcohol (NOBA) and glyceryl trinitrate (GTN). HCT 1026 and NCX 2057 undergo rapid ubiquitous carboxyl ester hydrolysis to their respective parent compounds and NOBA. The nitrate moiety of this latter is subsequently metabolized to inorganic nitrogen oxides (NOx), predominantly in liver cytosol by glutathione S-transferase (GST) and to a lesser extent in liver mitochondria. If, however, in liver cytosol, the carboxyl ester hydrolysis is prevented by an esterase inhibitor, the metabolism at the nitrate moiety level does not occur. In blood plasma, HCT 1026 and NCX 2057 are not metabolized to NOx, whereas a slow but sustained NO generation in deoxygenated whole blood as detected by electron paramagnetic resonance indicates the involvement of erythrocytes in the bioactivation of these compounds. Differently from NOBA, GTN is also metabolized in blood plasma and more quickly metabolized by different GST isoforms in liver cytosol. The cytosolic GST-mediated denitration of these organic nitrates in liver limits their interaction with other intracellular compartments to possible generation of NO and/or their subsequent availability and bioactivation in the systemic circulation and extrahepatic tissues. We show the possibility of modulating the activity of hepatic cytosolic enzymes involved in the metabolism of (nitrooxy)butyl ester compounds, thus increasing the therapeutic potential of this class of compounds.

Autoerotic accident by inhalation of propane-butane gas mixture.

We present a case of an accidental autoerotic death involving the inhalation of a propane-butane gas mixture, also known as LPG (liquefied petroleum gas). A 19-year-old male was found dead in supine position in his bed in a residential accommodation one day after he was last seen alive. On a personal computer at the end of the bed, a pornographic movie was still running. On his left shoulder, an empty rubber balloon and on the bedside 2 empty "Kisag-Gas" cartridges were found. Toxicologic investigations revealed an intoxication with propane and butane, together with a recent consumption of cannabis. This case report compares the toxicologic findings with other recently published cases, and the theories of the toxic effects are discussed.

3-(2-Ethoxy-4-{4-[3-hydroxy-2-methyl-4-(3-methylbutanoyl)phenoxy]butoxy}phenyl)propanoic acid: a brain penetrant allosteric potentiator at the metabotropic glutamate receptor 2 (mGluR2).

We have identified and synthesized a brain penetrant propanoic acid as an allosteric potentiator of the metabotropic glutamate receptor 2. Structure-activity relationship studies directed toward improving the potency, level of potentiation and brain penetration led to the discovery of 8 (EC50=1200 nM, 77% potentiation, 119% brain/plasma in rat, 20 mpk i.p., brain level of 5700 nM).