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ABSTRACT: Osteoarthritis (OA) is a complex disease plagued by a significant unmet need for treatment. To date, no disease- modifying OA drugs (DMOADs) exist and the available symptom-modifying OA drugs (SMOADs) have limitations. Although a complete understanding of the mechanisms of OA pain in humans is lacking, animal models have helped provide insight into the multifaceted origin and manifestation of OA pain. Success in discovering new therapeutics will likely require reliance on good animal models. This review summarizes the animal models available for studying pain associated with OA.
Current pharmaceutical biotechnology 04/2011; 12(10):1596-612. · 3.40 Impact Factor
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Qingyian Liu,
Wenyuan Qian,
Aiwen Li,
Kaustav Biswas,
Jian Jeffrey Chen,
Christopher Fotsch,
Nianhe Han,
Chester Yuan,
Leyla Arik,
Gloria Biddlecome,
Eileen Johnson,
Gondi Kumar,
Dianna Lester-Zeiner, Gordon Y Ng,
Randall W Hungate,
Benny C Askew
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ABSTRACT: The bradykinin B1 receptor has been shown to mediate pain response and is rapidly induced upon injury. Blocking this receptor may provide a promising treatment for inflammation and pain. We previously reported tetralin benzyl amines as potent B1 antagonists. Here we describe the synthesis and SAR of B1 receptor antagonists with homobenzylic amines. The SAR of different linkers led to the discovery of tetralin allylic amines as potent and selective B1 receptor antagonists (hB1 IC(50)=1.3 nM for compound 16). Some of these compounds showed modest oral bioavailability in rats.
Bioorganic & medicinal chemistry letters 08/2010; 20(15):4593-7. · 2.65 Impact Factor
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ABSTRACT: Mast cells (MCs) have important functional roles in leukocyte recruitment, pain, and wound healing, and increased tissue resident MC function has been associated with several fibrotic diseases. Consequently, the study of MCs in situ can be a direct approach to studying the pharmacodynamic impact of MC-directed therapeutics in tissues. Here we describe an automated laser scanning cytometry assay that was used to characterize the kinetics of MC accumulation in healing skin wounds and to study the effect of inhibiting CD117 (cKit) signaling. The number of tryptase-positive MCs approximately doubled 14 days after cutaneous injury in nonhuman primates. Treatment of animals with anti-CD117 or imatinib mesylate (Gleevec) reduced MC accumulation at the edge of healing wounds in mice and nonhuman primates, respectively. In translating this MC assay to become a biomarker for human studies, no differences in dermal MC numbers were evident between genders, ages or body mass index from 20 healthy donors. These data suggest that skin is a practical and useful tissue for tracking pharmacodynamic effects of MC-directed therapies.
Cytometry Part A 11/2008; 75(3):189-98. · 3.73 Impact Factor
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Roxanne K Kunz,
Shannon Rumfelt,
Ning Chen,
Dawei Zhang,
Andrew S Tasker,
Roland Bürli,
Randall Hungate,
Violeta Yu,
Yen Nguyen,
Douglas A Whittington,
Kristin L Meagher,
Matthew Plant,
Yanyan Tudor,
Michael Schrag,
Yang Xu, Gordon Y Ng,
Essa Hu
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ABSTRACT: Deregulation of the receptor tyrosine kinase c-Kit is associated with an increasing number of human diseases, including certain cancers and mast cell diseases. Interference of c-Kit signaling with multi-kinase inhibitors has been shown clinically to successfully treat gastrointestinal stromal tumors and mastocytosis. Targeted therapy of c-Kit activity may provide therapeutic advantages against off-target effects for non-oncology applications. A new structural class of c-Kit inhibitors is described, including in vitro c-Kit potency, kinase selectivity, and the observed binding mode.
Bioorganic & medicinal chemistry letters 08/2008; 18(18):5115-7. · 2.65 Impact Factor
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Ning Chen,
Roland W Bürli,
Susana Neira,
Randall Hungate,
Dawei Zhang,
Violeta Yu,
Yen Nguyen,
Yanyan Tudor,
Matthew Plant,
Shaun Flynn,
Kristin L Meagher,
Matthew R Lee,
Xuxia Zhang,
Andrea Itano,
Michael Schrag,
Yang Xu, Gordon Y Ng,
Essa Hu
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ABSTRACT: A potent and selective c-Kit inhibitor 20 was identified through a structure-activity relationship study. In an in vivo mouse model of mast cell activation, 20 blocked the SCF-induced histamine release with an EC(50) of 26 nM.
Bioorganic & medicinal chemistry letters 08/2008; 18(14):4137-41. · 2.65 Impact Factor
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Essa Hu,
Andrew Tasker,
Ryan D White,
Roxanne K Kunz,
Jason Human,
Ning Chen,
Roland Bürli,
Randall Hungate,
Perry Novak,
Andrea Itano,
Xuxia Zhang,
Violeta Yu,
Yen Nguyen,
Yanyan Tudor,
Matthew Plant,
Shaun Flynn,
Yang Xu,
Kristin L Meagher,
Douglas A Whittington, Gordon Y Ng
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ABSTRACT: Inhibition of c-Kit has the potential to treat mast cell associated fibrotic diseases. We report the discovery of several aminoquinazoline pyridones that are potent inhibitors of c-Kit with greater than 200-fold selectivity against KDR, p38, Lck, and Src. In vivo efficacy of pyridone 16 by dose-dependent inhibition of histamine release was demonstrated in a rodent pharmacodynamic model of mast cell activation.
Journal of Medicinal Chemistry 07/2008; 51(11):3065-8. · 5.25 Impact Factor
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Kaustav Biswas,
Aiwen Li,
Jian Jeffrey Chen,
Derin C D'Amico,
Christopher Fotsch,
Nianhe Han,
Jason Human,
Qingyian Liu,
Mark H Norman,
Bobby Riahi, [......],
Ming Huang,
Augustus Kamassah,
Richard Loeloff,
Hong Sun,
Feng-Yin Hsieh,
Gondi Kumar, Gordon Y Ng,
Randall W Hungate,
Benny C Askew,
Eileen Johnson
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ABSTRACT: The bradykinin B1 receptor is induced following tissue injury and/or inflammation. Antagonists of this receptor have been studied as promising candidates for treatment of chronic pain. We have identified aryl sulfonamides containing a chiral chroman diamine moiety that are potent antagonists of the human B1 receptor. Our previously communicated lead, compound 2, served as a proof-of-concept molecule, but suffered from poor pharmacokinetic properties. With guidance from metabolic profiling, we performed structure-activity relationship studies and have identified potent analogs of 2. Variation of the sulfonamide moiety revealed a preference for 3- and 3,4-disubstituted aryl sulfonamides, while bulky secondary and tertiary amines were preferred at the benzylic amine position for potency at the B1 receptor. Modifying the beta-amino acid core of the molecule lead to the discovery of highly potent compounds with improved in vitro pharmacokinetic properties. The most potent analog at the human receptor, compound 38, was also active in a rabbit B1 receptor cellular assay. Furthermore, compound 38 displayed in vivo activity in two rabbit models, a pharmacodynamic model with a blood pressure readout and an efficacy model of inflammatory pain.
Journal of Medicinal Chemistry 06/2007; 50(9):2200-12. · 5.25 Impact Factor
