Field evaluation of female- and male-targeted traps for Ceratitis capitata (Diptera: Tephritidae).

Mediterranean fruit fly (Medfly) Ceratitis capitata (Wiedemann) (Diptera: Tephritidae) is a globally significant economic pest for which lure based trapping can be used to monitor established populations and for surveillance. Either female- or male-targeted traps can be used; however, recommendations on which to apply are inconsistent and many programs rely on male-targeted traps. Here, we compare the performance of male-targeted traps (Lynfield Trap with Trimedlure) and female-targeted traps (Biotrap Globe trap with the 3-component lure-TMA Plus) in apple orchards in south-west Western Australia over 2 years (September 2019 to September 2021). Male-targeted traps caught more Medflies overall than female-targeted traps, although the difference was minor. However, female-targeted traps were better at attracting Medfly early in the season when populations were small; and were more likely to capture at least one fly when their paired male-targeted trap caught none. Conversely, male-targeted traps were more likely to capture Medflies late in the season and were more likely to catch high numbers of Medflies. Consequently, female-targeted traps may be better at detecting Medfly early in the season, and male-targeted traps may be better at detecting Medfly abundance late in the season, at least in apple orchards. Our results suggest that either or both trap-types could be used for monitoring Medfly populations, with the optimal solution being dependent on the intended application.

Using innovative tools for in vitro absorption, distribution, metabolism and excretion studies to efficiently and effectively support drug development.

Drug development is a complicated and lengthy process requiring a significant amount of intellectual and capital input, as well as extensive collaborations among various organizations and institutions. Contract research organizations play important roles at some or even all stages of the drug development process. To provide better service in in vitro drug absorption, disposition, metabolism and excretion studies, maintain data accuracy and promote work efficiency, we developed an integrated information system termed the 'Drug Metabolism Information System', and it is being used routinely by our drug metabolism department. The Drug Metabolism Information System assists scientists with assay design, data analysis and report drafting and thus reduces human error.

Discovery of Potent, Selective, and Peripherally Restricted Pan-Trk Kinase Inhibitors for the Treatment of Pain.

Hormones of the neurotrophin family, nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4), are known to activate the family of Tropomyosin receptor kinases (TrkA, TrkB, and TrkC). Moreover, inhibition of the TrkA kinase pathway in pain has been clinically validated by the NGF antibody tanezumab, leading to significant interest in the development of small molecule inhibitors of TrkA. Furthermore, Trk inhibitors having an acceptable safety profile will require minimal brain availability. Herein, we discuss the discovery of two potent, selective, peripherally restricted, efficacious, and well-tolerated series of pan-Trk inhibitors which successfully delivered three candidate quality compounds 10b, 13b, and 19. All three compounds are predicted to possess low metabolic clearance in human that does not proceed via aldehyde oxidase-catalyzed reactions, thus addressing the potential clearance prediction liability associated with our current pan-Trk development candidate PF-06273340.

Molecular hybridization yields triazole bronchodilators for the treatment of COPD.

A 1,2,4-triazole motif was employed as a bioisostere for the ester commonly used in muscarinic antagonists, and subsequent integrative conjugation to a ß2 agonist quinolinone furnished a new class of bifunctional MABAs for the treatment of COPD. Medicinal chemistry optimization using the principles of 'inhalation by design' furnished a clinical candidate with desirable pharmacological, pharmacokinetic and biopharmaceutical properties.

Inhalation by design: novel tertiary amine muscarinic M3 receptor antagonists with slow off-rate binding kinetics for inhaled once-daily treatment of chronic obstructive pulmonary disease.

A novel tertiary amine series of potent muscarinic M(3) receptor antagonists are described that exhibit potential as inhaled long-acting bronchodilators for the treatment of chronic obstructive pulmonary disease. Geminal dimethyl functionality present in this series of compounds confers very long dissociative half-life (slow off-rate) from the M(3) receptor that mediates very long-lasting smooth muscle relaxation in guinea pig tracheal strips. Optimization of pharmacokinetic properties was achieved by combining rapid oxidative clearance with targeted introduction of a phenolic moiety to secure rapid glucuronidation. Together, these attributes minimize systemic exposure following inhalation, mitigate potential drug-drug interactions, and reduce systemically mediated adverse events. Compound 47 (PF-3635659) is identified as a Phase II clinical candidate from this series with in vivo duration of action studies confirming its potential for once-daily use in humans.

Inhalation by design: dual pharmacology ß-2 agonists/M3 antagonists for the treatment of COPD.

This paper describes the successful design and development of dual pharmacology ß-2 agonists-M3 antagonists, for the treatment of chronic obstructive pulmonary disorder using the principles of 'inhalation by design'. A key feature of this work is the combination of balanced potency and pharmacodynamic duration with desirable pharmacokinetic and material properties, whilst keeping synthetic complexity to a minimum.

Inhalation by design: novel ultra-long-acting ß(2)-adrenoreceptor agonists for inhaled once-daily treatment of asthma and chronic obstructive pulmonary disease that utilize a sulfonamide agonist headgroup.

A novel series of potent and selective sulfonamide derived ß(2)-adrenoreceptor agonists are described that exhibit potential as inhaled ultra-long-acting bronchodilators for the treatment of asthma and chronic obstructive pulmonary disease. Analogues from this series mediate very long-lasting smooth muscle relaxation in guinea pig tracheal strips. The sulfonamide agonist headgroup confers high levels of intrinsic crystallinity that could relate to the acidic sulfonamide motif supporting a zwitterionic form in the solid state. Optimization of pharmacokinetic properties was achieved through targeted introduction of a phenolic moiety to support rapid phase II clearance, thereby minimizing systemic exposure following inhalation and reducing systemically mediated adverse events. Compound 38 (PF-610355) is identified as a clinical candidate from this series, with in vivo duration of action studies confirming its potential for once-daily use in humans. Compound 38 is currently in advanced phase II clinical studies.

Succinyl hydroxamates as potent and selective non-peptidic inhibitors of procollagen C-proteinase: design, synthesis, and evaluation as topically applied, dermal anti-scarring agents.

Succinyl hydroxamates 1 and 2 are disclosed as novel series of potent and selective inhibitors of procollagen C-proteinase (PCP) which may have potential as anti-fibrotic agents. Carboxamide 7 demonstrated good PCP inhibition and had excellent selectivity over MMPs involved in wound healing. In addition, 7 was effective in a cell-based model of collagen deposition (fibroplasia model) and was very effective at penetrating human skin in vitro. Compound 7 (UK-383,367) was selected as a candidate for evaluation in clinical studies as a topically applied, dermal anti-scarring agent.

The discovery of adamantyl-derived, inhaled, long acting beta(2)-adrenoreceptor agonists.

The design and profile of a series of adamantyl-containing long acting beta(2)-adrenoreceptor agonists are described. An optimal pharmacokinetic profile of low oral bioavailability was combined with a strong pharmacology profile when assessed using a guinea pig trachea tissue model. A focus was then placed on developing a robust synthetic route to ensure rapid delivery of material for clinical trials.

Potent and selective nonpeptidic inhibitors of procollagen C-proteinase.

6-Cyclohexyl-N-hydroxy-3-(1,2,4-oxadiazol-5-yl)hexanamides were previously disclosed as inhibitors of procollagen C-proteinase (PCP) culminating in the identification of amide 1. Our objective was to discover a second inhibitor that would have improved affinity for PCP and to optimize properties for transepidermal delivery (TED) to intact skin. Further investigation of this template identified a number of potent PCP inhibitors (IC50 values of 2-6 nM) with improved TED flux. Sulfonamide 56 had excellent PCP enzyme activity when measured with a peptide substrate (Ki 8.7 nM) or with the endogenous substrate procollagen (IC50 3.4 nM) and demonstrates excellent selectivity over MMPs involved in wound healing (>10 000-fold). In the fibroplasia model, 56 inhibited deposition of insoluble collagen by 76 +/- 2% at 10 microM and was very effective at penetrating human skin in vitro with a TED flux of 1.5 microg/cm2/h, which compares favorably with values for agents that are known to penetrate skin well in vivo. Based on this profile, 56 (UK-421,045) was selected as a candidate for further preclinical evaluation as a topically applied, dermal anti-scarring agent.

The discovery of long acting beta2-adrenoreceptor agonists.

The design and profile of a series of saligenin containing long acting beta(2)-adrenoreceptor agonists is described. Evaluation of these analogues using a guinea-pig tissue model demonstrates that analogues within this series have significantly longer durations of action than salmeterol and have the potential for a once daily profile in human.

The design and synthesis of a novel series of indole derived selective ET(A) antagonists.

Conformational constraint has been used as the key design element in the identification of a series of potent and selective ET(A) antagonists. The most potent antagonist, 32, (ET(A) IC(50)=0.55nM) is 722-fold selective over the ET(B) receptor, as measured by binding experiments.

Effects of Morphine on Free Radical-induced Apoptosis of Human Neuroblastoma SH-SY5Y Cells / 대한마취과학회지

BACKGROUND: The effect of opioids on nitric oxide (NO)- and peroxynitrite-induced neuronal cell death is largely unknown. In the present study, we examined the effect of morphine on NO- and peroxynitrite-induced cell death using a human neuroblastoma SH-SY5Y cell line, which abundantly expresses micro, delta, kappa-opioid receptors. METHODS: The cultured cells were pretreated with morphine and exposed to 3-morpholinosydnonimine (SIN-1) that simultaneously generates NO and superoxide, thus possibly forming peroxynitrite. The cell damage was assessed by using MTT assay and crystal violet staining. Morphological nuclear changes and enzymatic evidences of apoptosis of the cells after exposure to SIN-1 for 24 hours were evaluated by using 4', 6-diamidino-2-phenylindole (DAPI) staining and the measurement of pro-apoptotic protease (caspase-3) activity, respectively. Levels of reduced glutathion (GSH) were measured by monochloronimane (MCB) assay. RESULTS: Pretreatment of SH-SY5Y with morphine significantly inhibited the apoptotic cell death. Morphine also inhibited SIN-1-induced caspase-3 (pro-apoptotic protease) activity in a dose-dependent manner. However, naloxone (20 microM) could not antagonize completely the effect of morphine in SIN- 1-induced cell death. Pre-administered GSH and N-acetylcysteine (NAC) have been found to protect SIN-induced apoptosis, and the neuroblastoma cells treated with morphine had significantly elevated the levels of GSH. CONCLUSIONS: The present study shows that morphine protects the human neuroblastoma cell line SH- SY5Y from peroxynitrite-induced apoptotic cell death through elevated GSH levels. The protective actionof morphine seems to be associated with inhibition of the apoptotic pathway. However, it is suggested that morphine protects the cells possibly via other unknown mechanisms in addition to the activation of opioid receptors.