Quinolinyl-based multitarget-directed ligands with soluble epoxide hydrolase and fatty acid amide hydrolase inhibitory activities: Synthetic studies and pharmacological evaluations
Jeannes Angelia,
Leah Duong,
Faye Yun,
Anesa Mesic,
Cassandra Yuan,
Daniel Carr,
Siena Gunari,
Paula K. Hudson,
Christophe Morisseau,
Bruce D. Hammock,
Ram Kandasamy,
Stevan Pecic
Affiliations
Jeannes Angelia
Department of Chemistry & Biochemistry, California State University, Fullerton, 800 N. State College, Fullerton, CA, 92834, United States
Leah Duong
Department of Chemistry & Biochemistry, California State University, Fullerton, 800 N. State College, Fullerton, CA, 92834, United States
Faye Yun
Department of Chemistry & Biochemistry, California State University, Fullerton, 800 N. State College, Fullerton, CA, 92834, United States
Anesa Mesic
Department of Chemistry & Biochemistry, California State University, Fullerton, 800 N. State College, Fullerton, CA, 92834, United States
Cassandra Yuan
Department of Psychology, California State University, East Bay, 25800 Carlos Bee Blvd. Science S229, Hayward, CA, 94542, United States
Daniel Carr
Department of Psychology, California State University, East Bay, 25800 Carlos Bee Blvd. Science S229, Hayward, CA, 94542, United States
Siena Gunari
Department of Psychology, California State University, East Bay, 25800 Carlos Bee Blvd. Science S229, Hayward, CA, 94542, United States
Paula K. Hudson
Department of Chemistry & Biochemistry, California State University, Fullerton, 800 N. State College, Fullerton, CA, 92834, United States
Christophe Morisseau
Department of Entomology and Nematology, and UCD Comprehensive Cancer Center, University of California Davis, Davis, CA, 95616, United States
Bruce D. Hammock
Department of Entomology and Nematology, and UCD Comprehensive Cancer Center, University of California Davis, Davis, CA, 95616, United States
Ram Kandasamy
Department of Psychology, California State University, East Bay, 25800 Carlos Bee Blvd. Science S229, Hayward, CA, 94542, United States; Corresponding author.
Stevan Pecic
Department of Chemistry & Biochemistry, California State University, Fullerton, 800 N. State College, Fullerton, CA, 92834, United States; Corresponding author.
Simultaneous inhibition of soluble epoxide hydrolase (sEH) and fatty acid amide hydrolase (FAAH) with a single small molecule represents a novel therapeutic approach in treating inflammatory pain, since both targets are involved in pain and inflammation processes. In this study using multi-target directed ligands methodology we designed and synthesized 7 quinolinyl-based dual sEH/FAAH inhibitors, using an optimized microwave-assisted Suzuki-Miyaura coupling reaction and tested their potency in human FAAH and human, rat, and mouse sEH inhibition assays. The structure-activity relationship study showed that quinolinyl moiety is well tolerated in the active sites of both enzymes, yielding several very potent dual sEH/FAAH inhibitors with the IC50 values in the low nanomolar range. The most potent dual inhibitor 4d was further evaluated in stability assay in human and rat plasma where it performed better than the standard Warfarin while in vivo study revealed that 1 mg/kg 4d can inhibit acute inflammatory pain in male rats to a similar degree as the traditional nonsteroidal anti-inflammatory drug ketoprofen (30 mg/kg) after intraperitoneal injection. ADMET prediction studies for this dual inhibitor show favorable pharmacokinetic properties which will guide the future in vivo evaluations.
