Design, synthesis, molecular modeling, and biological evaluation of acrylamide derivatives as potent inhibitors of human dihydroorotate dehydrogenase for the treatment of rheumatoid arthritis
| Autor: | Tiantian Qi, Letian Zhang, Tingyuan Yang, Yating Luo, Shiliang Li, Fanxun Zeng, Lili Zhu, Guantian Yang, Yingfan Liang, Honglin Li, Rui Wang, Xiaoyong Xu |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
EA
ethyl acetate Molecular model PhMe toluene RA rheumatoid arthritis DMF N N-dimethylformamide DMSO dimethyl sulfoxide Pharmacology DCE 1 2-dichloroethane chemistry.chemical_compound 0302 clinical medicine DMARDs disease-modifying antirheumatic drugs TsCl tosyl chloride HRMS high-resolution mass spectrometry DMAP 4-dimethylaminopyridine TEA triethylamine CIA collagen-induced arthritis NBS N-bromosuccinimide DHODH dihydroorotate dehydrogenase LCMS liquid chromatography mass spectrometry General Pharmacology Toxicology and Pharmaceutics AML acute myeloid leukemia Benzoic acid 0303 health sciences IBD inflammatory bowel disease Chemistry NSAIDs non-steroidal anti-inflammatory drugs DCM dichloromethane PE petroleum ether HPLC high performance liquid chromatography 030220 oncology & carcinogenesis Acrylamide Original Article PDA photodiode array detector Lead compound NCS N-chlorosuccinimide THF tetrahydrofuran De novo pyrimidine biosynthesis PK pharmacokinetic MS multiple sclerosis TFA trifluoroacetic acid 03 medical and health sciences BPO benzoyl peroxide Pharmacokinetics In vivo LAH lithium aluminium hydride Potency Rheumatoid arthritis DHODH inhibitors 030304 developmental biology Acrylamide derivatives lcsh:RM1-950 DHODH SEL systemic lupus erythematosus FMN flavin mononucleotide lcsh:Therapeutics. Pharmacology Dihydroorotate dehydrogenase MeOH methanol |
| Zdroj: | Acta Pharmaceutica Sinica B, Vol 11, Iss 3, Pp 795-809 (2021) Acta Pharmaceutica Sinica. B |
| ISSN: | 2211-3835 |
| Popis: | Human dihydroorotate dehydrogenase (DHODH) is a viable target for the development of therapeutics to treat cancer and immunological diseases, such as rheumatoid arthritis (RA), psoriasis and multiple sclerosis (MS). Herein, a series of acrylamide-based novel DHODH inhibitors as potential RA treatment agents were designed and synthesized. 2-Acrylamidobenzoic acid analog 11 was identified as the lead compound for structure−activity relationship (SAR) studies. The replacement of the phenyl group with naphthyl moieties improved inhibitory activity significantly to double-digit nanomolar range. Further structure optimization revealed that an acrylamide with small hydrophobic groups (Me, Cl or Br) at the 2-position was preferred. Moreover, adding a fluoro atom at the 5-position of the benzoic acid enhanced the potency. The optimization efforts led to potent compounds 42 and 53‒55 with IC50 values of 41, 44, 32, and 42 nmol/L, respectively. The most potent compound 54 also displayed favorable pharmacokinetic (PK) profiles and encouraging in vivo anti-arthritic effects in a dose-dependent manner. Graphical abstract Dihydroorotate dehydrogenase (DHODH) is an attracting target for the treatment of immunological diseases. A series of acrylamide-based novel DHODH inhibitors as potential rheumatoid arthritis (RA) treatment agents were designed and synthesized, among which 54 is the most potent one with good pharmacokinetic profiles and favorable in vivo anti-arthritic effects.Image 1 |
| Databáze: | OpenAIRE |
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