Design, Synthesis, Structure–Activity Relationship Studies, and Three-Dimensional Quantitative Structure–Activity Relationship (3D-QSAR) Modeling of a Series of O-Biphenyl Carbamates as Dual Modulators of Dopamine D3 Receptor and Fatty Acid Amide Hydrolase

Abstract

We recently reported molecules designed according to the multitarget-directed ligand paradigm to exert combined activity at human fatty acid amide hydrolase (FAAH) and dopamine receptor subtype D3 (D3R). Both targets are relevant for tackling several types of addiction (most notably nicotine addiction) and other compulsive behaviors. Here, we report an SAR exploration of a series of biphenyl-N-[4-[4-(2,3-substituted-phenyl)piperazine-1-yl]alkyl]carbamates, a novel class of molecules that had shown promising activities at the FAAH-D3R target combination in preliminary studies. We have rationalized the structural features conducive to activities at the main targets and investigated activities at two off-targets: dopamine receptor subtype D2 and endocannabinoid receptor CB To understand the unexpected affinity for the CB receptor, we devised a 3D-QSAR model, which we then prospectively validated. Compound 33 was selected for PK studies because it displayed balanced affinities for the main targets and clear selectivity over the two off-targets. 33 has good stability and oral bioavailability and can cross the blood-brain barrier.

<p>Fullerene Derivatives as Lung Cancer Cell Inhibitors: Investigation of Potential Descriptors Using QSAR Approaches</p>

“…The QSAR can provide predictive models based on mathematical and statistical relations that can be used to optimize the design of known types of chemical drugs to achieve an improved activity. 21,22 However, there are still very few studies focused on the design of nanomedicines with the assistance of QSAR or other CADD techniques. 23 Here, we explored the potential of developing predictive computer models for a series of water-soluble fullerene derivatives acting as inhibitors of NSCLC cancer cells.…”

Design and Potency of Dual Soluble Epoxide Hydrolase/Fatty Acid Amide Hydrolase Inhibitors

“…Several multitarget inhibitors/modulators have been proposed for FAAH inhibition, including cyclooxygenase (COX), 17 , 18 monoacylglycerol lipase (MAGL), 19 cytosolic phospholipase A2, 20 , 21 and the dopamine 3 receptor. 22 When FAAH and COX inhibition were combined, the resulting drug not only improves the potency relative to targeting a single molecule but also reduces gastrointestinal side effects associated with nonsteroidal anti-inflammatory drugs. 17 In addition to these targets, soluble epoxide hydrolase (sEH) similarly synergizes with FAAH to improve potency on both inflammatory and neuropathic models of pain.…”

A computationally designed binding mode flip leads to a novel class of potent tri-vector cyclophilin inhibitors

“…The majority of the compounds were prepared according to Scheme 1 (steps a–d, see ESI† for details). Substituted amino derivatives were typically prepared from 4-nitrophenyl derivatives by reductive amination,27 or nucleophilic substitution 28. The urea moiety was prepared by condensation of the resulting amines with ethyl isocyanatoacetate,15 and the desired products were obtained by subsequent reduction of the nitro group 29…”