Spiroquinazolinones as novel, potent, and selective PDE7 inhibitors. Part 1

Lorthiois, Edwige; Bernardelli, Patrick; Vergne, Fabrice; Oliveira, Chrystelle; Mafroud, Abdel-Kader; Proust, Emmanuelle; Heuze, Lamia; Moreau, F.; Idrissi, Moulay; Tertre, Anita; Bertin, Bernadette; Coupe, Magali; Wrigglesworth, Roger; Descours, Arnaud; Soulard, Patricia; Berna, Patrick

doi:10.1016/j.bmcl.2004.07.011

Cited by 44 publications

(19 citation statements)

References 18 publications

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“…The data set is characterized by a high structural diversity since it is formed by iminothiadiazoles, 28,29 benzene sulfonamides, 30 quinazolines, 16 thiazoles, 31 and spirotricyclic derivatives, 32 among others (Figure 1). …”

mentioning

confidence: 99%

Identification in Silico and Experimental Validation of Novel Phosphodiesterase 7 Inhibitors with Efficacy in Experimental Autoimmune Encephalomyelitis Mice

Redondo

Palomo

Brea

et al. 2012

ACS Chem. Neurosci.

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A neural network model has been developed to predict the inhibitory capacity of any chemical structure to be a phosphodiesterase 7 (PDE7) inhibitor, a new promising kind of drugs for the treatment of neurological disorders. The numerical definition of the structures was achieved using CODES program. Through the validation of this neural network model, a novel family of 5-imino-1,2,4-thiadiazoles (ITDZs) has been identified as inhibitors of PDE7.Experimental extensive biological studies have demonstrated the ability of ITDZs to inhibit PDE7 and to increase intracellular levels of cAMP. Among them, the derivative 15 showed a high in vitro potency with desirable pharmacokinetic profile (safe genotoxicity and blood brain barrier penetration). Administration of ITDZ 15 in an experimental autoimmune encephalomyelitis (EAE) mouse model results in a significant attenuation of clinical symptoms, showing the potential of ITDZs, especially compound 15, for the effective treatment of multiple sclerosis.

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confidence: 99%

Identification in Silico and Experimental Validation of Novel Phosphodiesterase 7 Inhibitors with Efficacy in Experimental Autoimmune Encephalomyelitis Mice

Redondo

Palomo

Brea

et al. 2012

ACS Chem. Neurosci.

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“…All the 54 molecules reported by Lorthiois and coworkers 24,25 were used for docking studies. Analysis of various PDE isoform cocrystals by Zhang et al revealed that a ''hydrophobic clamp'' comprising the conserved aromatic residue at the roof of the binding site and a hydrophobic residue below contributes significantly to binding affinities.…”

Section: Docking Resultsmentioning

confidence: 99%

“…24,25 The molecules had a broad range of activities against PDE7 in vitro, with IC 50 ranging from 9.5 lM to 3.5 nM. The IC 50 values of the inhibitors were converted into pIC 50 by taking negative logarithm of IC 50 .…”

Section: Data Seriesmentioning

confidence: 99%

“…In this work, we studied structural and electronic similarities among the PDE7 inhibitors reported by Lorthiois and coworkers, 24,25 with the aim of identifying the characteristics that distinguish between potent and weak inhibitors. We generated virtual binding conformations for the spiroquinazolones using molecular docking.…”

Section: Introductionmentioning

confidence: 99%

“…1), a spiroquinazolinone which inhibited PDE7 with an IC 50 of 0.17 lM. 24 However, this compound is very hydrophobic. Optimization of this key lead compound was performed in search of a potent, selective, and soluble PDE7 inhibitor with acceptable pharmacokinetic properties.…”

Section: Introductionmentioning

confidence: 99%

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Stereoelectronic properties of spiroquinazolinones in differential PDE7 inhibitory activity

Daga

Doerksen

2008

J Comput Chem

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A detailed computational study on a series of spiroquinazolinones showing phosphodiesterase 7 (PDE7) inhibitory activity was performed to understand the binding mode and the role of stereoelectronic properties in binding. Our docking studies reproduced the essential hydrogen bonding and hydrophobic interactions for inhibitors of this class of enzymes. The N1 proton of the quinazolinone scaffold was involved in H-bonding to an amide side chain of the conserved glutamine residue in the active site. The central bicyclic ring of the molecules showed hydrophobic and pi-stacking interactions with hydrophobic and aromatic amino acid residues, respectively, present in the PDE7 active site. The docked conformations were optimized with density functional theory (DFT) and DFT electronic properties were calculated. Comparison of molecular electrostatic potential (MEP) plots of inhibitors with the active site of PDE7 suggested that the electronic distribution in the molecules is as important as steric factors for binding of the molecules to the receptor. The hydrogen bonding ability and nucleophilic nature of N1 appeared to be important for governing the interaction with PDE7. For less active inhibitors (pIC(50) < 6.5), the MEP maximum at N1 of the spiroquinazolinone ring was high or low based on the electronic properties of the substituents. All the more active molecules (pIC(50) > 6.5) had MEP highest at N3, not N1. Efficient binding of these inhibitors may need some rearrangement of side chains of active-site residues, especially Asn365. This computational modeling study should aid in design of new molecules in this class with improved PDE7 inhibition.

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cAMP‐Specific Phosphodiesterases: Modulation, Inhibition, and Activation

Cameron

Baillie

2012

Therapeutic Targets

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Spiroquinazolinones as novel, potent, and selective PDE7 inhibitors. Part 1

Cited by 44 publications

References 18 publications

Identification in Silico and Experimental Validation of Novel Phosphodiesterase 7 Inhibitors with Efficacy in Experimental Autoimmune Encephalomyelitis Mice

Identification in Silico and Experimental Validation of Novel Phosphodiesterase 7 Inhibitors with Efficacy in Experimental Autoimmune Encephalomyelitis Mice

Stereoelectronic properties of spiroquinazolinones in differential PDE7 inhibitory activity

cAMP‐Specific Phosphodiesterases: Modulation, Inhibition, and Activation

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