期刊
ACTA PHARMACEUTICA SINICA B
卷 11, 期 3, 页码 795-809出版社
INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
DOI: 10.1016/j.apsb.2020.10.008
关键词
DHODH; De novo pyrimidine biosynthesis; DHODH inhibitors; Acrylamide derivatives; Rheumatoid arthritis
资金
- National Key Research and Development Program (China) [2017YFD0200505, 2016YFA0502304]
- National Natural Science Foundation of China [81825020, 81803437]
- National Science & Technology Major Project Key New Drug Creation and Manufacturing Program (China) [2018ZX09711002]
- Fundamental Research Funds for the Central Universities
- Shanghai Foundation of Science and Technology [15431902100]
- Shanghai Sailing Program (China) [18YF1405100]
- National Program for Special Supports of Eminent Professionals
- National Program for Support of Top-Notch Young Professionals, China
Human DHODH is a promising target for cancer and autoimmune disease treatment. Novel DHODH inhibitors were designed and synthesized, with compound 11 identified as lead for SAR studies. Optimization efforts led to potent compounds with promising anti-arthritic effects in vivo.
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. (C) 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
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