Applying a multitarget rational drug design strategy: the first set of modulators with potent and balanced activity toward dopamine D3 receptor and fatty acid amide hydrolase

Simone, Alessio De; Ruda, G.F.; Albani, Clara; Tarozzo, Glauco; Bandiera, Tiziano; Piomelli, Daniele; Cavalli, Andrea; Bottegoni, Giovanni

doi:10.1039/c4cc00967c

Cited by 22 publications

(23 citation statements)

References 36 publications

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“…The results obtained are reported in Tables and for series I and II, respectively. Regarding series I, (Table ) compound 5 , with an unsubstituted 2‐oxo‐benzimidazole core, was a potent D3R modulator with an EC 50 value of 7.9 nM; molecular modelling studies showed as it simultaneously engaged both the OBP and the SBP (Figure A), in line with previously reported simulations . At GSK‐3β, 5 showed an IC 50 value of 20.1 μM; the 2‐oxo‐benzimidazole moiety engaged the hinge region of the enzyme, forming the typical H‐bond pattern of kinase inhibitors, while the arylpiperazine group projected outside the pocket (Figure B).…”

Section: Figuresupporting

confidence: 82%

Multitarget Compounds for Bipolar Disorder: From Rational Design to Preliminary Pharmacokinetic Evaluation

et al. 2020

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Due to the complex and multifactorial nature of bipolar disorder (BD), single‐target drugs have traditionally provided limited relief with no disease‐modifying effects. In line with the polypharmacology paradigm, we attempted to overcome these limitations by devising two series of multitarget‐directed ligands endowed with both a partial agonist profile at dopamine receptor D3 (D3R) and inhibitory activity against glycogen synthase kinase 3 beta (GSK‐3β). These are two structurally unrelated targets that play independent, yet connected, roles in cognition and mood regulation. Two compounds (7 and 10) emerged as promising D3R/GSK‐3β multitarget‐directed ligands with nanomolar activity at D3R and low‐micromolar inhibition of GSK‐3β, thereby confirming, albeit preliminarily, the feasibility of our strategy. Furthermore, 7 showed promising drug‐like properties in stability and pharmacokinetic studies.

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Section: Figuresupporting

confidence: 82%

Multitarget Compounds for Bipolar Disorder: From Rational Design to Preliminary Pharmacokinetic Evaluation

et al. 2020

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“…Hek293 cells stably transfected with the h-FAAH-1 were used as enzyme source. The fluorescent assay to measure FAAH-1 activity was performed as previously described by De Simone et al [69].…”

Section: Fluorogenic H-faah1 In Vitro Assaymentioning

confidence: 99%

Potent α-amino-β-lactam carbamic acid ester as NAAA inhibitors. Synthesis and structure–activity relationship (SAR) studies

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Fiasella

Ortega

et al. 2016

European Journal of Medicinal Chemistry

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4-Cyclohexylbutyl-N-[(S)-2-oxoazetidin-3-yl]carbamate (3b) is a potent, selective and systemically active inhibitor of intracellular NAAA activity, which produces profound anti-inflammatory effects in animal models. In the present work, we describe structure-activity relationship (SAR) studies on 3-aminoazetidin-2-one derivatives, which have led to the identification of 3b, and expand these studies to elucidate the principal structural and stereochemical features needed to achieve effective NAAA inhibition. Investigations on the influence of the substitution at the β-position of the 2-oxo-3-azetidinyl ring as well as on the effect of size and shape of the carbamic acid ester side chain led to the discovery of 3ak, a novel inhibitor of human NAAA that shows an improved physicochemical and drug-like profile relative to 3b. This favourable profile, along with the structural diversity of the carbamic acid chain of 3b, identify this compound as a promising new tool to investigate the potential of NAAA inhibitors as therapeutic agents for the treatment of pain and inflammation.

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“…We exploited a ligand-based approach by combining the pharmacophoric features responsible for binding to BACE-1 and GSK-3b, such as a guanidino motif and a cyclic amide group, respectively, into a single scaffold ( Figure 1). We subsequently performed structure-based docking simulations [15] to study the interactions of triazinonebased compounds with the catalytic pocket of both enzymes ( Figure 2). We subsequently performed structure-based docking simulations [15] to study the interactions of triazinonebased compounds with the catalytic pocket of both enzymes ( Figure 2).…”

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Multitarget Drug Discovery for Alzheimer's Disease: Triazinones as BACE‐1 and GSK‐3β Inhibitors

et al. 2014

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Cumulative evidence strongly supports that the amyloid and tau hypotheses are not mutually exclusive, but concomitantly contribute to neurodegeneration in Alzheimer's disease (AD). Thus, the development of multitarget drugs which are involved in both pathways might represent a promising therapeutic strategy. Accordingly, reported here in is the discovery of 6-amino-4-phenyl-3,4-dihydro-1,3,5-triazin-2(1H)-ones as the first class of molecules able to simultaneously modulate BACE-1 and GSK-3β. Notably, one triazinone showed well-balanced in vitro potencies against the two enzymes (IC50 of (18.03±0.01) μM and (14.67±0.78) μM for BACE-1 and GSK-3β, respectively). In cell-based assays, it displayed effective neuroprotective and neurogenic activities and no neurotoxicity. It also showed good brain permeability in a preliminary pharmacokinetic assessment in mice. Overall, triazinones might represent a promising starting point towards high quality lead compounds with an AD-modifying potential.

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Applying a multitarget rational drug design strategy: the first set of modulators with potent and balanced activity toward dopamine D3 receptor and fatty acid amide hydrolase

Cited by 22 publications

References 36 publications

Multitarget Compounds for Bipolar Disorder: From Rational Design to Preliminary Pharmacokinetic Evaluation

Multitarget Compounds for Bipolar Disorder: From Rational Design to Preliminary Pharmacokinetic Evaluation

Potent α-amino-β-lactam carbamic acid ester as NAAA inhibitors. Synthesis and structure–activity relationship (SAR) studies

Multitarget Drug Discovery for Alzheimer's Disease: Triazinones as BACE‐1 and GSK‐3β Inhibitors

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