2020
DOI: 10.1021/acschemneuro.0c00024
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Discovery and Optimization of Chromone Derivatives as Novel Selective Phosphodiesterase 10 Inhibitors

Abstract: Phosphodiesterase 10 (PDE10) inhibitors have received much attention as promising therapeutic agents for central nervous system (CNS) disorders such as schizophrenia and Huntington’s disease. Recently, a hit compound 1 with a novel chromone scaffold has shown moderate inhibitory activity against PDE10A (IC50 = 500 nM). Hit-to-lead optimization has resulted in compound 3e with an improved inhibitory activity (IC50 = 6.5 nM), remarkable selectivity (>95-fold over other PDEs), and good metabolic stability (RLM t … Show more

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Cited by 14 publications
(9 citation statements)
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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%
“…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%
“…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%
See 1 more Smart Citation
“…(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%