Amine-free melanin-concentrating hormone receptor 1 antagonists: Novel 1-(1H-benzimidazol-6-yl)pyridin-2(1H)-one derivatives and design to avoid CYP3A4 time-dependent inhibition

Igawa, Hideyuki; Takahashi, Masashi; Shirasaki, Mikio; Kakegawa, Keiko; Kina, Asato; Ikoma, Minoru; Aida, Jumpei; Yasuma, Tsuneo; Okuda, Suguru; Kawata, Y.; Noguchi, Toshihiro; Yamamoto, Satoshi; Fujioka, Yasushi; Kundu, Mrinalkanti; Khamrai, Uttam; Nakayama, Masaharu; Nagisa, Yasutaka; Kasai, Shizuo; Maekawa, Taira

doi:10.1016/j.bmc.2016.04.011

Cited by 9 publications

(4 citation statements)

References 44 publications

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“…Because, currently, there is no CYP3A4 TDI data set publicly available, we first built the CYP3A4 TDI data set. A total of 623 compounds (581 TDI vs 42 non-TDI) with experimental data was manually extracted from 85 research papers. − From the PubChem data set (PubChem AID 1851), we collected 7454 compounds as the negative samples. After pretreatment, 7914 unique compounds were finally obtained to form the data set (Data S1).…”

Section: Resultsmentioning

confidence: 99%

Development of In Silico Models for Predicting Potential Time-Dependent Inhibitors of Cytochrome P450 3A4

et al. 2022

Mol. Pharmaceutics

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Cytochrome P450 3A4 (CYP3A4) is one of the major drug metabolizing enzymes in the human body and metabolizes ∼30–50% of clinically used drugs. Inhibition of CYP3A4 must always be considered in the development of new drugs. Time-dependent inhibition (TDI) is an important P450 inhibition type that could cause undesired drug–drug interactions. Therefore, identification of CYP3A4 TDI by a rapid convenient way is of great importance to any new drug discovery effort. Here, we report the development of in silico classification models for prediction of potential CYP3A4 time-dependent inhibitors. On the basis of the CYP3A4 TDI data set that we manually collected from literature and databases, both conventional machine learning and deep learning models were constructed. The comparisons of different sampling strategies, molecular representations, and machine-learning algorithms showed the benefits of a balanced data set and the deep-learning model featured by GraphConv. The generalization ability of the best model was tested by screening an external data set, and the prediction results were validated by biological experiments. In addition, several structural alerts that are relevant to CYP3A4 time-dependent inhibitors were identified via information gain and frequency analysis. We anticipate that our effort would be useful for identification of potential CYP3A4 time-dependent inhibitors in drug discovery and design.

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Section: Resultsmentioning

confidence: 99%

Development of In Silico Models for Predicting Potential Time-Dependent Inhibitors of Cytochrome P450 3A4

et al. 2022

Mol. Pharmaceutics

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“…The following nitroanilines were obtained according to the published procedures: 1a [15], 1b [15], 1c [12f], 1d [16], 1j [17], 1 k [18], and 1o [12d]. Nitroanilines 1i and 1l were commercial.…”

Section: Methodsmentioning

confidence: 99%

Synthesis of various 1‐alkylbenzimidazole derivatives directly from 2‐alkylaminonitroarenes via a two‐step, one‐pot procedure

Walewska‐Królikiewicz,

Wilk,

Kwast

et al. 2024

Journal of Heterocyclic Chem

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N‐Alkyl‐2‐nitroanilines deoxygenated with tributylphosphine form intermediate 2‐(alkylamino)aryliminophosphoranes, which were subjected, without isolation, to various cyclocondensation reactions with CS2, CO2, alkyl isocyanates, acyl chlorides, anhydrides, or esters. A simple, convenient, one‐pot procedure provided derivatives of unsymmetrically substituted 1‐alkylbenzimidazoles functionalized at C2 in good to excellent yields. The method does not require the use of metals, sensitive catalysts, or pressure.

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“…Compound 512 displayed prominent MCH receptor 1(MCH-R1) binding affinity (IC 50 = 1 nM), as well as low human ether-a-go-go-related gene (hERG) binding affinity thereby ensuring low risks of cardiovascular diseases, metabolic stability and preferable pharmacokinetic profile ( Lim et al, 2013 ). Igawa et al synthesized several 1-(1H-benzimidazol-6-yl) pyridin-2(1H)-one compounds among which compound 513 showed most prominent antagonistic property against MCH-R1 ( Igawa et al, 2016 ).…”

Section: Biological Activitiesmentioning

confidence: 99%

A Comprehensive Account on Recent Progress in Pharmacological Activities of Benzimidazole Derivatives

et al. 2021

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Nowadays, nitrogenous heterocyclic molecules have attracted a great deal of interest among medicinal chemists. Among these potential heterocyclic drugs, benzimidazole scaffolds are considerably prevalent. Due to their isostructural pharmacophore of naturally occurring active biomolecules, benzimidazole derivatives have significant importance as chemotherapeutic agents in diverse clinical conditions. Researchers have synthesized plenty of benzimidazole derivatives in the last decades, amidst a large share of these compounds exerted excellent bioactivity against many ailments with outstanding bioavailability, safety, and stability profiles. In this comprehensive review, we have summarized the bioactivity of the benzimidazole derivatives reported in recent literature (2012–2021) with their available structure-activity relationship. Compounds bearing benzimidazole nucleus possess broad-spectrum pharmacological properties ranging from common antibacterial effects to the world’s most virulent diseases. Several promising therapeutic candidates are undergoing human trials, and some of these are going to be approved for clinical use. However, notable challenges, such as drug resistance, costly and tedious synthetic methods, little structural information of receptors, lack of advanced software, and so on, are still viable to be overcome for further research.

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Amine-free melanin-concentrating hormone receptor 1 antagonists: Novel 1-(1H-benzimidazol-6-yl)pyridin-2(1H)-one derivatives and design to avoid CYP3A4 time-dependent inhibition

Cited by 9 publications

References 44 publications

Development of In Silico Models for Predicting Potential Time-Dependent Inhibitors of Cytochrome P450 3A4

Development of In Silico Models for Predicting Potential Time-Dependent Inhibitors of Cytochrome P450 3A4

Synthesis of various 1‐alkylbenzimidazole derivatives directly from 2‐alkylaminonitroarenes via a two‐step, one‐pot procedure

A Comprehensive Account on Recent Progress in Pharmacological Activities of Benzimidazole Derivatives

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