Discovery and Optimization of Orally Bioavailable Phthalazone and Cinnolone Carboxylic Acid Derivatives as S1P2 Antagonists against Fibrotic Diseases

Mammoliti, Oscar; Jansen, Koen; Bkassiny, Sandy El; Palisse, Adeline; Triballeau, Nicolas; Bucher, Denis; Allart, Brigitte; Jaunet, Alex; Tricarico, Giovanni; Wachter, Maxim De; Menet, Christel J.; Blanc, J. C. Yves Le; Letfus, Vatroslav; Rupčić, Renata; Šmehil, Mario; Poljak, Tanja; Coornaert, Beatrice; Sonck, K.; Duys, Inge; Waeckel, Ludovic; Lecru, Lola; Marsais, Florence; Jagerschmidt, Catherine; Auberval, Marielle; Pujuguet, Philippe; Oste, Line; Borgonovi, Monica; Wakselman, Emanuelle; Christophe, Thierry; Houvenaghel, Nicolas; Jans, Mia; Heckmann, Bertrand; Sanière, Laurent; Brys, Reginald

doi:10.1021/acs.jmedchem.1c01066

Cited by 10 publications

(5 citation statements)

References 74 publications

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“…, lymphoid tissues and spleen) . Over the past few years, S1PR2 has been identified as a potential therapeutic target and S1PR2 antagonists were developed as therapeutic agents for the treatment of inflammation, multiple sclerosis (MS), and fibrotic diseases, representative structures are shown in Figure . − JTE-013 is the first reported S1PR2 antagonist and has been widely used in defining the biological roles of S1PR2 in various disease . In our previous study, JTE-013 showed promising 5-FU-resistance reversal activity in primary 5-FU-resistant HCT116 DPD cells, whereas it exhibited moderate effect in SW620/5-FU cells, which acquired its resistance from the continuous treatment of 5-FU .…”

Section: Introductionmentioning

confidence: 99%

Rational Design, Synthesis, and Biological Evaluation of Novel S1PR2 Antagonists for Reversing 5-FU-Resistance in Colorectal Cancer

et al. 2022

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Resistance to 5-FU reduces its clinical efficacy for the treatment of colorectal cancer. Sphingosine-1-phosphate receptor 2 (S1PR2) has emerged as a potential target to reverse 5-FU-resistance by inhibiting the expression of dihydropyrimidine dehydrogenase (DPD). In this study, 38 novel S1PR2 antagonists based on aryl urea structure were designed and synthesized, and the structure−activity relationship was investigated based on the S1PR2 binding assay. Representative compound 43 potently interacts with S1PR2 with a K D value of 0.73 nM. It displays potent 5-FU resensitizing activity in multiple 5-FU-resistant tumor cell lines, particularly in SW620/5-FU (EC 50 = 1.99 ± 0.03 μM) but shows no cytotoxicity in the normal colon cell line NCM460 up to 1000 μM. Moreover, 43 significantly enhances the antitumor efficacy of 5-FU in the SW620/5-FU animal model. These data suggest that 43 could be a novel lead compound for developing a 5-FU resensitizing agent.

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Section: Introductionmentioning

confidence: 99%

Rational Design, Synthesis, and Biological Evaluation of Novel S1PR2 Antagonists for Reversing 5-FU-Resistance in Colorectal Cancer

et al. 2022

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“…In 2021, another series of phthalazone and quinolone carboxylic acid analogs was reported by Mammoliti and coworkers from weak fragment hits through a structure-based design strategy (Figure 20). 132 In the beginning, they analyzed the substructure features in reported S1PR2 antagonists and agonists and found that two types of skeleton structure, including diaryl ketone and diaryl amide, were recurring. Consequently, they searched their compound collection containing these two structures, and identified compound 37 as a novel S1PR2 antagonist hit with modest S1PR2 antagonist activity (IC 50 > 8 μM) in the Ca 2+ assay in hS1PR2-overexpressing CHO cells.…”

Section: Phthalazone and Quinolone Carboxylic Acid Analogsmentioning

confidence: 99%

An overview of sphingosine‐1‐phosphate receptor 2: Structure, biological function, and small‐molecule modulators

Hao,

Luo,

Jiang

et al. 2024

Medicinal Research Reviews

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Over the past decade, there has been a notable increase in research on sphingosine‐1‐phosphate receptor 2 (S1PR2), which is a type of G‐protein‐coupled receptor. Upon activation by S1P or other ligands, S1PR2 initiates downstream signaling pathways such as phosphoinositide 3‐kinase (PI3K), Mitogen‐activated protein kinase (MAPK), Rho/Rho‐associated coiled‐coil containing kinases (ROCK), and others, contributing to the diverse biological functions of S1PR2 and playing a pivotal role in various physiological processes and disease progressions, such as multiple sclerosis, fibrosis, inflammation, and tumors. Due to the extensive biological functions of S1PR2, many S1PR2 modulators, including agonists and antagonists, have been developed and discovered by pharmaceutical companies (e.g., Novartis and Galapagos NV) and academic medicinal chemists for disease diagnosis and treatment. However, few reviews have been published that comprehensively overview the functions and regulators of S1PR2. Herein, we provide an in‐depth review of the advances in the function of S1PR2 and its modulators. We first summarize the structure and biological function of S1PR2 and its pathological role in human diseases. We then focus on the discovery approach, design strategy, development process, and biomedical application of S1PR2 modulators. Additionally, we outline the major challenges and future directions in this field. Our comprehensive review will aid in the discovery and development of more effective and clinically applicable S1PR2 modulators.

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“…[4] 5-Pyridonyl-indazole derivative exhibits good sphingosine-1-phosphate receptor 2 (S1P2) inhibitory activity and in vivo anti-idiopathic pulmonary fibrosis potency. [5] The N-myristoyl transferase inhibitors with this scaffold achieve the full cures in a mouse model of African sleeping sickness. [6] Owing to their importance, the direct functionalization of 2H-indazoles becomes highly desirable to medicinal chemistry and organic chemistry.…”

Section: Introductionmentioning

confidence: 99%

C-3 Functionalization of 2-Aryl-2H-indazoles under Photo/Electrocatalysis

Wang¹,

Wang²,

Ma³

et al. 2022

Chinese Journal of Organic Chemistry

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2H-Indazole is a privileged scaffold widely existing in drugs and bioactive molecules. The C-H functionalization of 2H-indazole is the cutting edge in medicinal chemistry and organic chemistry. Compared with traditional synthetic methods, the visible light/electrochemical-promoted synthetic method has mild conditions and is an environmentally friendly synthetic strategy. The C-H functionalization of 2-aryl-2H-indazoles at the C-3 position catalyzed by photochemical/electrochemical strategies in recent years is summarized in terms of catalytic systems, with special emphasis on the corresponding reaction mechanism, which might inspire the further development of new catalytic methods.

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Discovery and Optimization of Orally Bioavailable Phthalazone and Cinnolone Carboxylic Acid Derivatives as S1P2 Antagonists against Fibrotic Diseases

Cited by 10 publications

References 74 publications

Rational Design, Synthesis, and Biological Evaluation of Novel S1PR2 Antagonists for Reversing 5-FU-Resistance in Colorectal Cancer

Rational Design, Synthesis, and Biological Evaluation of Novel S1PR2 Antagonists for Reversing 5-FU-Resistance in Colorectal Cancer

An overview of sphingosine‐1‐phosphate receptor 2: Structure, biological function, and small‐molecule modulators

C-3 Functionalization of 2-Aryl-2H-indazoles under Photo/Electrocatalysis

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