Discovery and Optimization of Chromone Derivatives as Novel Selective Phosphodiesterase 10 Inhibitors

Yu, Yan-Fa; Zhang, Chen; Huang, Yi‐You; Zhang, Sirui; Zhou, Qian; Li, Xiangmin; Lai, Zengwei; Li, Zhe; Gao, Yuqi; Wu, Yinuo; Guo, Lei; Wu, Deyan; Luo, Hai‐Bin

doi:10.1021/acschemneuro.0c00024

Cited by 14 publications

(9 citation statements)

References 55 publications

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“…Based on the inclusion criteria, 11 diverse compounds with IC50 for PDE1B ranging from 0.06 nM to 70 nM as well as 29 molecules with IC50 of 0.008 nM to 64 nM for PDE10A were chosen as the training set. [47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64] The remaining 8 PDE1B and 9 PDE10A inhibitors obtained which were structurally diverse chemical compounds from the training set served as the test set to assess the predictive ability of the resultant pharmacophore. By using the merged feature pharmacophore generation method, a total of 10 pharmacophore models were synthesized for both targets, where the models with the highest t score were selected.…”

Section: Design Of Novel Selective Pde1b and Pde10a Inhibitorsmentioning

confidence: 99%

New Dual PDE1B and PDE10A Inhibitors Identified via Ligand-Based Pharmacophore Modelling and Virtual Screening

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Gaurav

Gautam

2023

Preprint

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Context Schizophrenia is a chronic neuropsychiatric disorder affecting over 1% of the world population. Current antipsychotic therapy shows inadequacy in mitigating the negative and cognitive symptoms, besides causing undesirable extrapyramidal side effects. Inhibition of PDE1B and PDE10A simultaneously can mitigate positive, negative, and cognitive symptoms. Thus, this study was aimed at identifying new dual PDE1B and PDE10A inhibitors using ligand-based pharmacophore modelling, virtual screening, and molecular docking. Pharmacophore models for PDE1B and PDE10A produced Gunner-Henry (GH) scores of 0.83 and 0.71, respectively. Pharmacophore model based virtual screening and molecular docking led to the identification of UNPD167314 as the lead compound with good binding affinity for PDE1B (-8.4 kcal/mol) and PDE10A (-9.7 kcal/mol). The binding interactions include hydrophobic interactions with P-clamp and hydrogen bonding with invariant glutamine. Structural modifications resulted in the design of 51 novel inhibitors, with compound 18 exhibiting the highest binding affinity for both PDE1B (-10.6 kcal/mol) and PDE10A (-11.7 kcal/mol) following substitution of tertbutyl at R1, hydroxyl at R2, and carboxyl at R3. Methods LigandScout 4.4.8 was used to generate, validate, and refine the ligand-based pharmacophore models for PDE1B and PDE10A, followed by sequential virtual screening of the Universal Natural Products Database. The hits were screened further using DruLiTo software to ensure BBB penetration. Pan Assay Interference Compounds were removed using PAINS-Remover server. SwissADME and PreADMET were used to deduce pharmacokinetic parameters of the screened compounds. Finally, Molecular docking and visualization of the dual hits were performed using Autodock Vina 1.2.0, followed by structural modifications to improve interaction affinity.

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Section: Design Of Novel Selective Pde1b and Pde10a Inhibitorsmentioning

confidence: 99%

New Dual PDE1B and PDE10A Inhibitors Identified via Ligand-Based Pharmacophore Modelling and Virtual Screening

Soon

Gaurav

Gautam

2023

Preprint

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“…Compound 129 is a novel PDE10 inhibitor with an IC 50 of 6.5 nM (Figure 10A). 155 Initially, a hit compound 127 was identified through the HTS of a library of molecules. Next, the isosteric replacement of metabolically unstable −H at the C-6 position (chromone ring) with a halogen atom and replacement of thiophene with phenyl improved the inhibitory activity against PDE10A, with IC 50 values in the range of 17−54 nM (128a−128e).…”

Section: G Protein-coupled Receptor-52mentioning

confidence: 99%

“…Compound 129 is a novel PDE10 inhibitor with an IC 50 of 6.5 nM (Figure A) . Initially, a hit compound 127 was identified through the HTS of a library of molecules.…”

Section: Small-molecule Candidates Under Preclinical Investigation Fo...mentioning

confidence: 99%

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The Emerging Landscape of Small-Molecule Therapeutics for the Treatment of Huntington’s Disease

Ahamad

Bhat

2022

J. Med. Chem.

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Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene (HTT). The new insights into HD's cellular and molecular pathways have led to the identification of numerous potent small-molecule therapeutics for HD therapy. The field of HD-targeting small-molecule therapeutics is accelerating, and the approval of these therapeutics to combat HD may be expected in the near future. For instance, preclinical candidates such as naphthyridine-azaquinolone, AN1, AN2, CHDI-00484077, PRE084, EVP4593, and LOC14 have shown promise for further optimization to enter into HD clinical trials. This perspective aims to summarize the advent of small-molecule therapeutics at various stages of clinical development for HD therapy, emphasizing their structure and design, therapeutic effects, and specific mechanisms of action. Further, we have highlighted the key drivers involved in HD pathogenesis to provide insights into the basic principle for designing promising anti-HD therapeutic leads.

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“…(Kandhare et al, 2012;Kumar et al, 2010) Recently, the chromanone skeleton (as well its derivatives) F I G U R E 1 Classical NO-donor drugs for vasodilation has become a highly advantageous skeleton for the design and development of new PDE inhibitors, which had high PDE5 inhibitory activity (Figure 3). (Wu et al, 2017;Wu et al, 2018;Yu et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, and biological evaluation of novel NO‐releasing 4‐chromanone derivatives as potential vasodilator agents

et al. 2022

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The nitric oxide/cyclic guanosine monophosphate (NO/cGMP) signaling pathway is an effective mechanism involved in the treatment of hypertension. In our search for potential antihypertensive agents, a series of novel NO‐donor derivatives of the 4‐chromanone skeleton were designed and synthesized by coupling furoxans or nitrooxy NO‐donor moieties. All derivatives showed enhanced nitric oxide releasing capacity and vasodilator activity with EC50 values ranging from 0.0215 μM to 1.46 μM, obviously superior to those of precursor 3. These biological evaluations indicated that all compounds displayed an important vasorelaxant effect, and several compounds (9c, 14b, 14c, 14d) presented good vasodilator activity, with 14c being the best. Furthermore, molecular modeling studies revealed that compound 14c occupied the pocket well with the phosphodiesterase 5 domain in a favorable conformation. In conclusion, we observed that these novel compounds can act as structural templates for the design and subsequent development of new vasodilators and antihypertensive drugs.

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Discovery and Optimization of Chromone Derivatives as Novel Selective Phosphodiesterase 10 Inhibitors

Cited by 14 publications

References 55 publications

New Dual PDE1B and PDE10A Inhibitors Identified via Ligand-Based Pharmacophore Modelling and Virtual Screening

New Dual PDE1B and PDE10A Inhibitors Identified via Ligand-Based Pharmacophore Modelling and Virtual Screening

The Emerging Landscape of Small-Molecule Therapeutics for the Treatment of Huntington’s Disease

Design, synthesis, and biological evaluation of novel NO‐releasing 4‐chromanone derivatives as potential vasodilator agents

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