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Scott D Kuduk,
Ronald K Chang,
Christina N Di Marco,
Robert M Dipardo,
Sean P Cook, Matthew J Cato,
Aneta Jovanovska,
Mark O Urban,
Michael Leitl,
Robert H Spencer,
Stefanie A Kane,
George D Hartman,
Mark T Bilodeau
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ABSTRACT: A series of benzothiophene methyl amines were examined in an effort to identify non-amidine chemotypes with reduced polypharmacology from existing leads with the goal of finding potent ASIC3 channel blockers to advance the therapeutic evaluation of ASIC3 inhibition.
Bioorganic & medicinal chemistry letters 05/2011; 21(14):4255-8. · 2.65 Impact Factor
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Scott E Wolkenberg,
Zhijian Zhao,
James J Mulhearn,
Scott T Harrison,
John M Sanders, Matthew J Cato,
Aneta Jovanovska,
Jacqueline Panigel,
Sean P Cook,
Darrell A Henze,
Stefanie A Kane,
George D Hartman,
James C Barrow
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ABSTRACT: The Merck Fragment Library was screened versus acid-sensing ion channel 3 (ASIC3), a novel target for the treatment of pain. Fragment hits were optimized using two strategies, and potency was improved from 0.7 mM to 3 μM with retention of good ligand efficiency and incorporation of reasonable physical properties, off-target profile, and rat pharmacokinetics.
Bioorganic & medicinal chemistry letters 12/2010; 21(9):2646-9. · 2.65 Impact Factor
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ABSTRACT: Inflammatory pain is triggered by activation of pathways leading to the release of mediators such as bradykinin, prostaglandins, interleukins, ATP, growth factors and protons that sensitize peripheral nociceptors. The activation of acid-sensitive ion channels (ASICs) may have particular relevance in the development and maintenance of inflammatory pain. ASIC3 is of particular interest due to its restricted tissue distribution in the nociceptive primary afferent fibres and its high sensitivity to protons.
To examine the contribution of ASIC3 to the development and maintenance of muscle pain and inflammatory pain, we studied the in vivo efficacy of a selective ASIC3 inhibitor, APETx2, in rats.
Administration of APETx2 into the gastrocnemius muscle prior to the administration of low pH saline prevented the development of mechanical hypersensitivity, whereas APETx2 administration following low-pH saline was ineffective in reversing hypersensitivity. The prevention of mechanical hypersensitivity produced by acid administration was observed whether APETx2 was applied via i.m. or i.t. routes. In the complete Freund's adjuvant (CFA) inflammatory pain model, local administration of APETx2 resulted in a potent and complete reversal of established mechanical hypersensitivity, whereas i.t. application of APETx2 was ineffective.
ASIC3 contributed to the development of mechanical hypersensitivity in the acid-induced muscle pain model, whereas ASIC3 contributed to the maintenance of mechanical hypersensitivity in the CFA inflammatory pain model. The contribution of ASIC3 to established hypersensitivity associated with inflammation suggests that this channel may be an effective analgesic target for inflammatory pain states.
British Journal of Pharmacology 10/2010; 161(4):950-60. · 4.41 Impact Factor
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Scott D Kuduk,
Christina N Di Marco,
Vera Bodmer-Narkevitch,
Sean P Cook, Matthew J Cato,
Aneta Jovanovska,
Mark O Urban,
Michael Leitl,
Nova Sain,
Annie Liang,
Robert H Spencer,
Stefanie A Kane,
George D Hartman,
Mark T Bilodeau
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ABSTRACT: The synthesis, structure-activity relationship (SAR), and pharmacological evaluation of analogs of the acid-sensing ion channel (ASIC) inhibitor A-317567 are reported. It was found that the compound with an acetylenic linkage was the most potent ASIC-3 channel blocker. This compound reversed mechanical hypersensitivity in the rat iodoacetate model of osteoarthritis pain, although sedation was noted. Sedation was also observed in ASIC-3 knockout mice, questioning whether sedation and antinociception are mediated via a non-ASIC-3 specific mechanism.
ACS Chemical Neuroscience 01/2010; 1(1):19-24. · 3.68 Impact Factor
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Scott D Kuduk,
Ronald K Chang,
Jenny M-C Wai,
Christina N Di Marco,
Victoria Cofre,
Robert M DiPardo,
Sean P Cook, Matthew J Cato,
Aneta Jovanovska,
Mark O Urban,
Michael Leitl,
Robert H Spencer,
Stefanie A Kane,
George D Hartman,
Mark T Bilodeau
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ABSTRACT: A series of indole amidines modified at the 2-position of the indole ring were evaluated as inhibitors of Acid-Sensing Ion Channel-3 (ASIC3), a novel target for the treatment of chronic pain.
Bioorganic & medicinal chemistry letters 07/2009; 19(15):4059-63. · 2.65 Impact Factor
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Scott D Kuduk,
Christina N Di Marco,
Ronald K Chang,
Robert M Dipardo,
Sean P Cook, Matthew J Cato,
Aneta Jovanovska,
Mark O Urban,
Michael Leitl,
Robert H Spencer,
Stefanie A Kane,
Mark T Bilodeau,
George D Hartman,
Mark G Bock
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ABSTRACT: A series of amiloride derivatives modified at the 5-position of the pyrazine ring were evaluated as inhibitors of acid-sensing ion channel-3 (ASIC3), a novel target for the treatment of chronic pain.
Bioorganic & medicinal chemistry letters 04/2009; 19(9):2514-8. · 2.65 Impact Factor
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Kausik K Nanda,
M Brad Nolt, Matthew J Cato,
Stefanie A Kane,
Laszlo Kiss,
Robert H Spencer,
Jixin Wang,
Joseph J Lynch,
Christopher P Regan,
Gary L Stump,
Bing Li,
Rebecca White,
Suzie Yeh,
Michael J Bogusky,
Mark T Bilodeau,
Christopher J Dinsmore,
Craig W Lindsley,
George D Hartman,
Scott E Wolkenberg,
B Wesley Trotter
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ABSTRACT: This letter describes the discovery of a novel series of potent Kv1.5 ion channel antagonists based on a diisopropyl amide scaffold. Structure-activity relationships of functionalized analogs are discussed. Key compound 1-(3-(diisopropylcarbamoyl)-2-phenyl-3-(pyridin-3-yl)propyl)-3-(2-fluorobenzyl)urea (10) exhibits significant atrial-selective effects in an in vivo model.
Bioorganic & Medicinal Chemistry Letters 12/2006; 16(22):5897-901. · 2.55 Impact Factor