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Design, synthesis, molecular modeling, and biological evaluation of acrylamide derivatives as potent inhibitors of human dihydroorotate dehydrogenase for the treatment of rheumatoid arthritis.

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العنوان: Design, synthesis, molecular modeling, and biological evaluation of acrylamide derivatives as potent inhibitors of human dihydroorotate dehydrogenase for the treatment of rheumatoid arthritis.
المؤلفون: Zeng F; Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China., Li S; Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China., Yang G; Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China., Luo Y; Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China., Qi T; Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China., Liang Y; Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China., Yang T; Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China., Zhang L; Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China., Wang R; Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China., Zhu L; Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China., Li H; Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China., Xu X; Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China.
المصدر: Acta pharmaceutica Sinica. B [Acta Pharm Sin B] 2020 Oct 15. Date of Electronic Publication: 2020 Oct 15.
Publication Model: Ahead of Print
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Elsevier Country of Publication: Netherlands NLM ID: 101600560 Publication Model: Print-Electronic Cited Medium: Print ISSN: 2211-3835 (Print) Linking ISSN: 22113835 NLM ISO Abbreviation: Acta Pharm Sin B
أسماء مطبوعة: Original Publication: [Amsterdam] : Elsevier, 2011-
مستخلص: 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 IC 50 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.
(© 2020 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)
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فهرسة مساهمة: Keywords: AML, acute myeloid leukemia; Acrylamide derivatives; BPO, benzoyl peroxide; CIA, collagen-induced arthritis; DCE, 1,2-dichloroethane; DCM, dichloromethane; DHODH; DHODH inhibitors; DHODH, dihydroorotate dehydrogenase; DMAP, 4-dimethylaminopyridine; DMARDs, disease-modifying antirheumatic drugs; DMF, N,N-dimethylformamide; DMSO, dimethyl sulfoxide; De novo pyrimidine biosynthesis; EA, ethyl acetate; FMN, flavin mononucleotide; HPLC, high performance liquid chromatography; HRMS, high-resolution mass spectrometry; IBD, inflammatory bowel disease; LAH, lithium aluminium hydride; LCMS, liquid chromatography mass spectrometry; MS, multiple sclerosis; MeOH, methanol; NBS, N-bromosuccinimide; NCS, N-chlorosuccinimide; NSAIDs, non-steroidal anti-inflammatory drugs; PDA, photodiode array detector; PE, petroleum ether; PK, pharmacokinetic; PhMe, toluene; RA, rheumatoid arthritis; Rheumatoid arthritis; SEL, systemic lupus erythematosus; TEA, triethylamine; TFA, trifluoroacetic acid; THF, tetrahydrofuran; TsCl, tosyl chloride
تواريخ الأحداث: Date Created: 20201020 Latest Revision: 20240222
رمز التحديث: 20240223
مُعرف محوري في PubMed: PMC7558257
DOI: 10.1016/j.apsb.2020.10.008
PMID: 33078092
قاعدة البيانات: MEDLINE
الوصف
تدمد:2211-3835
DOI:10.1016/j.apsb.2020.10.008