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Michael P Maher,
Anindya Bhattacharya,
Hong Ao,
Nadia Swanson,
Nyan-Tsz Wu,
Jamie Freedman,
Mena Kansagara,
Brian Scott,
Dong H Li,
William A Eckert, [......], Kia Sepassi,
Michele Rizzolio,
Anne Fitzgerald,
Jing Liu,
Bryan J Branstetter,
Jason C Rech,
Alec D Lebsack,
J Guy Breitenbucher,
Alan D Wickenden,
Sandra R Chaplan
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ABSTRACT: As an integrator of multiple nociceptive and/or inflammatory stimuli, TRPV1 is an attractive therapeutic target for the treatment of various painful disorders. Several TRPV1 antagonists have been advanced into clinical trials and the initial observations suggest that TRPV1 antagonism may be associated with mild hyperthermia and thermal insensitivity in man. However, no clinical efficacy studies have been described to date, making an assessment of risk:benefit impossible. Furthermore, it is not clear whether these early observations are representative of all TRPV1 antagonists and whether additional clinical studies with novel TRPV1 antagonists are required in order to understand optimal compound characteristics. In the present study we describe 2-(2,6-dichloro-benzyl)-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine (JNJ-39729309) as a novel, TRPV1 antagonist. JNJ-39729209 displaced tritiated resiniferotoxin binding to TRPV1 and prevented TRPV1 activation by capsaicin, protons and heat. In-vivo, JNJ-39729209 blocked capsaicin-induced hypotension, induced a mild hyperthermia and inhibited capsaicin-induced hypothermia in a dose dependent manner. JNJ-39729209 showed significant efficacy against carrageenan- and CFA-evoked thermal hyperalgesia and exhibited significant anti-tussive activity in a guinea-pig model of capsaicin-induced cough. In pharmacokinetic studies, JNJ-39729209 was found to have low clearance, a moderate volume of distribution, good oral bioavailability and was brain penetrant. On the basis of these findings, JNJ-39729209 represents a structurally novel TRPV1 antagonist with potential for clinical development. The advancement of JNJ-39729209 into human clinical trials could be useful in further understanding the analgesic potential of TRPV1 antagonists.
European journal of pharmacology 08/2011; 663(1-3):40-50. · 2.59 Impact Factor
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Terrance D Barrett,
Heather L Palomino,
Theresa I Brondstetter,
Kimon C Kanelakis,
Xiaodong Wu,
Peter V Haug,
Wen Yan,
Andrew Young,
Hong Hua,
Juliet C Hart,
Da-Thao Tran,
Hariharan Venkatesan,
Mark D Rosen,
Hillary M Peltier, Kia Sepassi,
Michele C Rizzolio,
Scott D Bembenek,
Tara Mirzadegan,
Michael H Rabinowitz,
Nigel P Shankley
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ABSTRACT: The hypoxia-inducible factor (HIF) prolyl hydroxylase (PHD) enzymes represent novel targets for the treatment of anemia, ulcerative colitis, and ischemic and metabolic disease inter alia. We have identified a novel small-molecule inhibitor of PHD, 1-(5-chloro-6-(trifluoromethoxy)-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid (JNJ-42041935), through structure-based drug design methods. The pharmacology of JNJ-42041935 was investigated in enzyme, cellular, and whole-animal systems and was compared with other compounds described in the literature as PHD inhibitors. JNJ-42041935, was a potent (pK(I) = 7.3-7.9), 2-oxoglutarate competitive, reversible, and selective inhibitor of PHD enzymes. In addition, JNJ-42041935 was used to compare the effect of selective inhibition of PHD to intermittent, high doses (50 μg/kg i.p.) of an exogenous erythropoietin receptor agonist in an inflammation-induced anemia model in rats. JNJ-42041935 (100 μmol/kg, once a day for 14 days) was effective in reversing inflammation-induced anemia, whereas erythropoietin had no effect. The results demonstrate that JNJ-42041935 is a new pharmacological tool, which can be used to investigate PHD inhibition and demonstrate that PHD inhibitors offer great promise for the treatment of inflammation-induced anemia.
Molecular pharmacology 03/2011; 79(6):910-20. · 4.53 Impact Factor
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Michael A Letavic,
Leah Aluisio,
John R Atack,
Pascal Bonaventure,
Nicholas I Carruthers,
Christine Dugovic,
Anita Everson,
Mark A Feinstein,
Ian C Fraser,
Kenway Hoey, [......],
Brian Lord,
Timothy W Lovenberg,
Kiev S Ly,
Kirsten L Morton,
S Timothy Motley,
Diane Nepomuceno,
Michele Rizzolio,
Raymond Rynberg, Kia Sepassi,
Jonathan Shelton
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ABSTRACT: The pre-clinical characterization of novel aryloxypyridine amides that are histamine H(3) receptor antagonists is described. These compounds are high affinity histamine H(3) ligands that penetrate the CNS and occupy the histamine H(3) receptor in rat brain. Several compounds were extensively profiled pre-clinically leading to the identification of two compounds suitable for nomination as development candidates.
Bioorganic & medicinal chemistry letters 07/2010; 20(14):4210-4. · 2.65 Impact Factor
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ABSTRACT: The purpose of this study is to account for thermodynamic variations due to changes in the physical environment of propellant-based systems, particularly metered dose inhalers (MDIs). Twenty organic compounds were measured via differential scanning calorimetry under ambient pressure, 60 psi, and 90 psi. The increase in pressure did not affect the melting point of any of the compounds. A modest increase (approximately 8%) in enthalpy of fusion was noted. This correlates to a modest increase in entropy of fusion, and thus ideal crystalline solubility, though the magnitude of this change depends primarily on the melting point of the given compound. Because the relationship between melting point and solubility is logarithmic, compounds with higher melting points are affected more by this increased energy of melting. Based on the findings, modest changes can be made to predictive models to estimate solubility in propellant systems to account for changes in the physical environment of MDIs.
Drug Development and Industrial Pharmacy 10/2008; 34(9):930-5. · 1.49 Impact Factor
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ABSTRACT: The GSE (General Solubility Equation) and AQUAFAC (Aqueous Functional Group Activity Coefficients) are two empirical models for aqueous solubility prediction. This study compares the aqueous solubility estimation of a set of 1642 pharmaceutically and environmentally related compounds, using the two methods. The average absolute errors in the solubility prediction are 0.543 log units for AQUAFAC and 0.576 log units for the GSE. About 88.0% of the AQUAFAC solubilities and 83.0% of the GSE molar aqueous solubilities are predicted within one log unit of the observed values. The marginally greater accuracy of AQUAFAC is due to the fact that it utilizes fitted-parameters for many structural fragments and is based on experimental solubility data. The GSE on the other hand is a simpler, non-regression based equation which uses two parameters for solubility prediction.
International Journal of Pharmaceutics 09/2008; 360(1-2):122-47. · 3.35 Impact Factor
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ABSTRACT: The objective of these studies was to examine the in vivo performance of oral formulations of chlorpropham (CIPC). In order to develop a new oral formulation several different solubilization techniques were evaluated, namely: cosolvents, surfactants, and complexing agents. The solubilization data indicated that a conventional solution formulation was not plausible. Two self-emulsifying drug delivery systems (SEDDS) were developed and evaluated for stability. Both SEDDS formulations were found to be chemically stable. In vivo analysis of a SEDDS formulation, a suspension formulation and an intravenous bolus dose was conducted in F344 rats. Pharmacokinetic analysis of the formulation data indicated that the SEDDS formulation provided only marginally better oral bioavailability compared to a suspension formulation. While SEDDS formulations often result in greater bioavailability this was not observed for CIPC. In vivo analysis indicate that CIPC results in a situation where the dissolution rate of CIPC from the suspension is not rate limiting, rather the absorption rate in the GI tract is rate-limiting. This paradigm is the result of CIPCs low melting point and the relatively small particle size of the suspension which facilitate the dissolution in the GI tract.
Journal of Pharmaceutical Sciences 04/2008; 97(12):5222-8. · 3.06 Impact Factor
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ABSTRACT: The octanol−air partition coefficient is commonly used to understand the extent of chemical partitioning between the atmosphere and organic matter in the environment. In this study, octanol−air partition coefficients were estimated by generating an expression from combining empirical equations for the molar octanol solubility and saturated vapor pressures of organic compounds. The resultant equation simply estimates octanol−air partition coefficients from boiling points, entropies of boiling, and heat capacity changes on boiling.
02/2007;
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ABSTRACT: The purpose of this work was to develop an equation to estimate the saturated vapor pressures of organic compounds at ambient temperature. A new equation based on the integrated form of the Clausius−Clapeyron equation was used to estimate the room temperature saturated vapor pressures of 815 organic compounds. It was found to reliably estimate vapor pressures over 15 orders of magnitude with an average absolute error of 0.18 logarithmic units, corresponding to a factor of 1.50.
11/2006;
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ABSTRACT: The purpose of this work was to derive an equation for the rapid estimation of octanol solubilities of organic compounds. Solubilities ranging over 4 orders of magnitude were predicted with an average absolute error of 0.39 logarithmic units using melting point alone. The greatest error in prediction occurred for strongly bonded compounds.
AAPS PharmSciTech 02/2006; 7(1):E26. · 1.43 Impact Factor
