Guo Zhu Zheng

Fatty acid amide hydrolase inhibitors display broad selectivity and inhibit multiple carboxylesterases as off-targets

Fatty acid amide hydrolase (FAAH) is the primary regulator of several bioactive lipid amides including anandamide. Inhibitors of FAAH are potentially useful for the treatment of pain, anxiety, depression, and other nervous system disorders. However, FAAH inhibitors must display selectivity for this enzyme relative to the numerous other serine hydrolases present in the human proteome in order to be therapeutically acceptable. Here we employed activity-based protein profiling (ABPP) to assess the selectivity of FAAH inhibitors in multiple rat and human tissues. We discovered that some inhibitors, including carbamate compounds SA-47 and SA-72, and AM404 are exceptionally selective while others, like URB597, BMS-1, OL-135, and LY2077855 are less selective, displaying multiple off-targets. Since proteins around 60kDa constitute the major off-targets for URB597 and several other FAAH inhibitors with different chemical structures, we employed the multi-dimensional protein identification technology (MudPIT) approach to analyze their identities. We identified multiple carboxylesterase isozymes as bona fide off-targets of FAAH inhibitors. Consistently, enzymatic assay confirmed inhibition of carboxylesterase activities in rat liver by FAAH inhibitors. Since carboxylesterases hydrolyze a variety of ester-containing drugs and prodrugs, we speculate that certain FAAH inhibitors, by inhibiting carboxylesterases, might have drug-drug interactions with other medicines if developed as therapeutic agents.

Tetrahydropyridine-4-carboxamides as novel, potent transient receptor potential vanilloid 1 (TRPV1) antagonists

A series of 1,2,3,6-tetrahydropyridyl-4-carboxamides, exemplified by 6, have been synthesized and evaluated for in vitro TRPV1 antagonist activity, and in vivo analgesic activity in animal pain models. The tetrahydropyridine 6 is a novel TRPV1 receptor antagonist that potently inhibits receptor-mediated Ca2+ influx in vitro induced by several agonists, including capsaicin, N-arachidonoyldopamine (NADA), and low pH. This compound penetrates the CNS and shows potent anti-nociceptive effects in a broad range of animal pain models upon oral dosing due in part to its ability to antagonize both central and peripheral TRPV1 receptors. The SAR leading to the discovery of 6 is presented in this report.

Adenosine kinase inhibitors: polar 7-substitutent of pyridopyrimidine derivatives improving their locomotor selectivity.

We have discovered that polar 7-substituents of pyridopyrimidine derivatives affect not only whole cell AK inhibitory potency, but also selectivity in causing locomotor side effects in vivo animal models. We have identified compound, 1o, which has potent whole cell AK inhibitory potency, analgesic activity and minimal reduction of locomotor activity.