Daniel Cortright

Publications (5)15.3 Total impact

• Article: Pyrido[2,3-b]pyrazines, discovery of TRPV1 antagonists with reduced potential for the formation of reactive metabolites.

  Kevin J Hodgetts, Charles A Blum, Timothy Caldwell, Rajagopal Bakthavatchalam, Xiaozhang Zheng, Scott Capitosti, James E Krause, Daniel Cortright, Marci Crandall, Beth Ann Murphy, Susan Boyce, A Brian Jones, Bertrand L Chenard
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  ABSTRACT: The transient receptor potential cation channel, subfamily V, member 1 (TRPV1) is a non-selective cation channel that can be activated by a wide range of noxious stimuli, including capsaicin, acid, and heat. Blockade of TRPV1 activation by selective antagonists is under investigation in an attempt to identify novel agents for pain treatment. During pre-clinical development, the 1,8-naphthyridine 2 demonstrated unacceptably high levels of irreversible covalent binding. Replacement of the 1,8-naphthyridine core by a pyrido[2,3-b]pyrazine led to the discovery of compound 26 which was shown to have significantly lower potential for the formation of reactive metabolites. Compound 26 was characterized as an orally bioavailable TRPV1 antagonist with moderate brain penetration. In vivo, 26 significantly attenuated carrageenan-induced thermal hyperalgesia (CITH) and dose-dependently reduced complete Freund's adjuvant (CFA)-induced chronic inflammatory pain after oral administration.
  Bioorganic & medicinal chemistry letters 08/2010; 20(15):4359-63. · 2.65 Impact Factor
• Article: Discovery of novel 6,6-heterocycles as transient receptor potential vanilloid (TRPV1) antagonists.

  Charles A Blum, Timothy Caldwell, Xiaozhang Zheng, Rajagopal Bakthavatchalam, Scott Capitosti, Harry Brielmann, Stéphane De Lombaert, Mark T Kershaw, David Matson, James E Krause, [......], Beth Ann Murphy, Susan Boyce, A Brian Jones, Glenn Mason, Wayne Rycroft, Helen Perrett, Rachael Conley, Nicola Burnaby-Davies, Bertrand L Chenard, Kevin J Hodgetts
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  ABSTRACT: The transient receptor potential cation channel, subfamily V, member 1 (TRPV1) is a nonselective cation channel that can be activated by a wide range of noxious stimuli, including capsaicin, acid, and heat. Blockade of TRPV1 activation by selective antagonists is under investigation in an attempt to identify novel agents for pain treatment. The design and synthesis of a series of novel TRPV1 antagonists with a variety of different 6,6-heterocyclic cores is described, and an extensive evaluation of the pharmacological and pharmacokinetic properties of a number of these compounds is reported. For example, the 1,8-naphthyridine 52 was characterized as an orally bioavailable and brain penetrant TRPV1 antagonist. In vivo, 52 fully reversed carrageenan-induced thermal hyperalgesia (CITH) in rats and dose-dependently potently reduced complete Freund's adjuvant (CFA) induced chronic inflammatory pain after oral administration.
  Journal of Medicinal Chemistry 03/2010; 53(8):3330-48. · 4.80 Impact Factor
• Article: Aminoquinazolines as TRPV1 antagonists: modulation of drug-like properties through the exploration of 2-position substitution.

  Charles A Blum, Xiaozhang Zheng, Harry Brielmann, Kevin J Hodgetts, Rajagopal Bakthavatchalam, Jayaraman Chandrasekhar, James E Krause, Daniel Cortright, David Matson, Marci Crandall, Chu K Ngo, Lawrence Fung, Marta Day, Mark Kershaw, Stéphane De Lombaert, Bertrand L Chenard
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  ABSTRACT: A focused SAR exploration of the lead 4-aminoquinazoline TRPV1 antagonist 2 led to the discovery of compound 18. In rats, compound 18 is readily absorbed following oral dosing and demonstrates excellent in vivo potency and efficacy in an acute inflammatory pain model.
  Bioorganic & medicinal chemistry letters 09/2008; 18(16):4573-7. · 2.65 Impact Factor
• Article: 1-Benzylbenzimidazoles: the discovery of a novel series of bradykinin B(1) receptor antagonists.

  Qin Guo, Jayaraman Chandrasekhar, David Ihle, David J Wustrow, Bertrand L Chenard, James E Krause, Alan Hutchison, Dawn Alderman, Charles Cheng, Daniel Cortright, Daniel Broom, Mark T Kershaw, Jean Simmermacher-Mayer, Yao Peng, Kevin J Hodgetts
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  ABSTRACT: The design, synthesis, and structure-activity studies of a novel series of BK B(1) receptor antagonists based on a 1-benzylbenzimidazole chemotype are described. A number of compounds, for example, 38g, with excellent affinity for the cynomolgus macaque and rat bradykinin B(1) receptor were discovered.
  Bioorganic & medicinal chemistry letters 09/2008; 18(18):5027-31. · 2.65 Impact Factor
• Article: From arylureas to biarylamides to aminoquinazolines: discovery of a novel, potent TRPV1 antagonist.

  Xiaozhang Zheng, Kevin J Hodgetts, Harry Brielmann, Alan Hutchison, Frank Burkamp, A Brian Jones, Peter Blurton, Robert Clarkson, Jayaraman Chandrasekhar, Rajagopal Bakthavatchalam, Stéphane De Lombaert, Marci Crandall, Daniel Cortright, Charles A Blum
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  ABSTRACT: Bioisosteric replacement of piperazine with an aryl ring in lead VR1 antagonist 1 led to the biarylamide series. The development of B-ring SAR led to the conformationally constrained analog 70. The resulting aminoquinazoline 70 represents a novel VR1 antagonist with improved in vitro potency and oral bioavailability vs the analogous compounds from the lead series.
  Bioorganic & Medicinal Chemistry Letters 11/2006; 16(19):5217-21. · 2.55 Impact Factor