Discovery of MK-4409, a Novel Oxazole FAAH Inhibitor for the Treatment of Inflammatory and Neuropathic Pain

  • ACS Med Chem Lett. 2014 Apr 10;5(6):717-21. doi: 10.1021/ml5001239.
Harry R Chobanian  1 ,  Yan Guo  1 ,  Ping Liu  1 ,  Marc D Chioda  1 ,  Selena Fung  1 ,  Thomas J Lanza  1 ,  Linda Chang  1 ,  Raman K Bakshi  1 ,  James P Dellureficio  1 ,  Qingmei Hong  1 ,  Mark McLaughlin  1 ,  Kevin M Belyk  1 ,  Shane W Krska  1 ,  Amanda K Makarewicz  1 ,  Elliot J Martel  1 ,  Joseph F Leone  1 ,  Lisa Frey  1 ,  Bindhu Karanam  1 ,  Maria Madeira  1 ,  Raul Alvaro  1 ,  Joyce Shuman  1 ,  Gino Salituro  1 ,  Jenna L Terebetski  1 ,  Nina Jochnowitz  1 ,  Shruti Mistry  1 ,  Erin McGowan  1 ,  Richard Hajdu  1 ,  Mark Rosenbach  1 ,  Catherine Abbadie  1 ,  Jessica P Alexander  1 ,  Lin-Lin Shiao  1 ,  Kathleen M Sullivan  1 ,  Ravi P Nargund  1 ,  Matthew J Wyvratt  1 ,  Linus S Lin  1 ,  Robert J DeVita  1
Affiliations
  • 1. Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Immunology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
PMID: 24944750 DOI: 10.1021/ml5001239
Abstract

We report herein the identification of MK-4409, a potent and selective fatty acid amide hydrolase (FAAH) inhibitor. Starting from a high throughput screening (HTS) hit, medicinal chemistry efforts focused on optimizing of FAAH inhibition in vitro potency, improving the pharmacokinetic (PK) profile, and increasing in vivo efficacy in rodent inflammatory and neuropathic pain assays.

Keywords
CNS; FAAH; Fatty acid amide hydrolase; MK-4409; enzyme; inflammatory pain; inhibitor; neuropathic pain; oxazole; pyrazole.
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