Structure-activity relationship studies and pharmacological evaluation of 4-phenylthiazoles as dual soluble epoxide hydrolase/fatty acid amide hydrolase inhibitors

Abstract

Forty-two 4-phenylthiazole analogs, organized in two libraries 4a-u and 6a-u, were prepared and biologically evaluated in human fatty acid amide hydrolase (FAAH), and human, rat and mouse soluble epoxide hydrolase (sEH) inhibition assays. This structure–activity relationship (SAR) study explores the impact of electronic and steric changes on the molecule’s potency and binding affinity to better understand the structural features important for dual sEH/FAAH inhibition which will guide the development of novel treatments for pain and inflammation. Our SAR revealed that electron-donating groups on the aromatic ring of the 4-phenylthiazole moiety are particularly well tolerated by both enzymes when placed at the ortho, meta and para positions; however, the overall 3D shape of the molecule is very important for the potent FAAH inhibition, suggesting more restricted size of the FAAH binding pocket compared to sEH binding pocket. Two selected dual inhibitors, 4p and 4s, were tested in the rat liver microsomes stability assays and evaluated in vivo in the formalin test. Systemic administration of 4p and 4s via intraperitoneal injection decreased nociceptive behavior (i.e., licking of the injected paw) in male rats, and this effect was dose-dependent for both compounds. Two doses, 1 and 3 mg/kg of 4p, decreased nociceptive behavior to a similar extent to that of 30 mg/kg ketoprofen, a traditional nonsteroidal anti-inflammatory drug. However, only 3 mg/kg of 4s decreased nociceptive behavior compared to vehicle-treated animals, and this effect was comparable to ketoprofen-treated animals. Taken together, these findings reveal the antinociceptive potential of 4-phenylthiazole-based dual FAAH and sEH inhibitors and suggest pharmacodynamic differences within this class of inhibitors despite similar potencies in vitro.