Addressing phototoxicity observed in a novel series of biaryl derivatives: Discovery of potent, selective and orally active phosphodiesterase 10A inhibitor ASP9436

Hamaguchi, Wataru; Masuda, Naoyuki; Miyamoto, Sadaaki; Kikuchi, Shigetoshi; Narazaki, Fumie; Shiina, Yasuhiro; Seo, Ryushi; Amano, Y.; Mihara, Takuma; Moriguchi, Hiroyuki; Hattori, Kouji

doi:10.1016/j.bmc.2015.04.052

Cited by 9 publications

(5 citation statements)

References 37 publications

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“…The X-ray crystal structure also disclosed that 2 does not interact with Tyr693 which was found to be important to increase PDE10A selectivity in previous studies. 18,28) For the purpose of preparing compounds having the interaction with Tyr693, fragment growing approach was adopted and introduction of heteroaromatics into 5-position of pyrazolopyrimidine ring was performed. In the course of preparing compounds capable of interacting with the Tyr693, the molecular weight of the compound would be considered to be increased which should cause the increase in the lipophilicity of the compounds.…”

Section: Resultsmentioning

confidence: 99%

Fragment-Based Discovery of Pyrimido[1,2-b]indazole PDE10A Inhibitors

et al. 2018

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In this study, we report the identification of potent pyrimidoindazoles as phosphodiesterase10A (PDE10A) inhibitors by using the method of fragment-based drug discovery (FBDD). The pyrazolopyridine derivative 2 was found to be a fragment hit compound which could occupy a part of the binding site of PDE10A enzyme by using the method of the X-ray co-crystal structure analysis. On the basis of the crystal structure of compound 2 and PDE10A protein, a number of compounds were synthesized and evaluated, by means of structure-activity relationship (SAR) studies, which culminated in the discovery of a novel pyrimidoindazole derivative 13 having good physicochemical properties.

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Section: Resultsmentioning

confidence: 99%

Fragment-Based Discovery of Pyrimido[1,2-b]indazole PDE10A Inhibitors

et al. 2018

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“…Compound 19 was reported as a phosphodiesterase 10A inhibitor with moderate inhibitory activity, improved metabolic stability, and an MPE of 0.21 in the 3T3 NRU PT, suggesting the potential for phototoxicity (Figure 14). 26 Removal of either the fused phenyl A-ring or the central Cring linker not only removed the phototoxic liability and enabled the team to highlight the problematic structural features related to the conjugated triaryl system but also introduced a loss of potency or metabolic instability, respectively. The phototoxic potential of this series was not predicted by ΔE HOMO−LUMO alone or by the dihedral angle of the B,C-biaryl system.…”

Section: Of a Conjugated System To Disrupt Orbital Overlapmentioning

confidence: 99%

“…In estimating the phototoxicity potential of a series of PDE10A inhibitors, Hamaguchi et al reported superior performance of flattening energy compared to using ΔE HOMO−LUMO alone. 26 In this case, flattening energy was defined as the energy difference between the energy-minimized conformation and the coplanar conformation of a biaryl motif, calculated by the semiempirical PM7 method. Nevertheless, the authors concluded that ΔE HOMO−LUMO is still an important complementary consideration with flattening energy for estimation of the phototoxicity risk in their study, especially when the contributions of structures other than biaryl motifs were assessed.…”

Section: Phototoxicity�convention and Recent Advancesmentioning

confidence: 99%

“…In estimating the phototoxicity potential of a series of PDE10A inhibitors, Hamaguchi et al reported superior performance of flattening energy compared to using Δ E HOMO–LUMO alone . In this case, flattening energy was defined as the energy difference between the energy-minimized conformation and the coplanar conformation of a biaryl motif, calculated by the semiempirical PM7 method.…”

Section: In Silico Modeling Of Phototoxicityconvention and Recent Ad...mentioning

confidence: 99%

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Phototoxicity─Medicinal Chemistry Strategies for Risk Mitigation in Drug Discovery

Harrison¹,

Chen²,

Yasoshima³

et al. 2023

J. Med. Chem.

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Phototoxicity is a common safety concern encountered by project teams in pharmaceutical research and has the potential to stop progression of an otherwise promising candidate molecule. This perspective aims to provide an overview of the approaches toward mitigation of phototoxicity that medicinal chemists have taken during the lead optimization phase in the context of regulatory standards for photosafety evaluation. Various strategies are laid out based on available literature examples in order to highlight how structural modification can be utilized toward successful mitigation of a phototoxicity liability. A proposed flowchart is presented as a guidance tool to be used by the practicing medicinal chemist when facing a phototoxicity risk. The description of available tools to consider in the drug design process will include an overview of the evolution of in silico methods and their application as well as structure alerts for consideration as potential phototoxicophores.

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“…Among these, 190 positive and 225 negative chemicals were obtained. For ex17a and ex17b in the data, the number of N bonds in the 5-membered ring in SMILES was four, which was corrected to three, as in an original paper by Hamaguchi et al (2015). The modified SMILES were Cn1cc(-c2ccncc2)c(OCc 2ccc(-c3nc4ccccc4n3C)cc2)n1 and Cn1cc(-c2ccncc2)c (OCc2ccc(-c3nc4ccc4n3C)cc2)n1, respectively.…”

Section: Data Preparationmentioning

confidence: 99%

Development of a GCN-based model to predict in vitro phototoxicity from the chemical structure and HOMO-LUMO gap

Igarashi

Re²,

Kojima

et al. 2023

J. Toxicol. Sci.

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The interaction between sunlight and drugs can lead to phototoxicity in patients who have received such drugs. Phototoxicity assessment is a regulatory requirement globally and one of the main toxicity screening steps in the early stages of drug discovery. An in silico-in vitro approach has been utilized mainly for toxicology assessments at these stages. Although several quantitative structure-activity relationship (QSAR) models for phototoxicity have been developed, in silico technology to evaluate phototoxicity has not been well established. In this study, we attempted to develop an artificial intelligence (AI) model to predict the in vitro Neutral Red Uptake Phototoxicity Test results from a chemical structure and its derived information. To accomplish this, we utilized an open-source software library, kMoL. kMoL employs a graph convolutional neural networks (GCN) approach, which allows it to learn the data for the specified chemical structure. kMoL also utilizes the integrated gradient (IG) method, enabling it to visually display the substructures contributing to any positive results. To construct this AI model, we used only the chemical structure as a basis, then added the descriptors and the HOMO-LUMO gap, which was obtained from quantum chemical calculations. As a result, the assortment of chemical structures and the HOMO-LUMO gap produced an AI model with high discrimination performance, and an F1 score of 0.857. Additionally, our AI model could visualize the substructures involved in phototoxicity using the IG method. Our AI model can be applied as a toxicity screening method and could enhance productivity in drug development.

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Addressing phototoxicity observed in a novel series of biaryl derivatives: Discovery of potent, selective and orally active phosphodiesterase 10A inhibitor ASP9436

Cited by 9 publications

References 37 publications

Fragment-Based Discovery of Pyrimido[1,2-<i>b</i>]indazole PDE10A Inhibitors

Fragment-Based Discovery of Pyrimido[1,2-<i>b</i>]indazole PDE10A Inhibitors

Phototoxicity─Medicinal Chemistry Strategies for Risk Mitigation in Drug Discovery

Development of a GCN-based model to predict <i>in vitro</i> phototoxicity from the chemical structure and HOMO-LUMO gap

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