2. Academic Validation
  3. Discovery of potent and orally bioavailable benzothiazole-benzenesulfonamide derivatives as ABCA1 upregulators for the management of dyslipidemia

Discovery of potent and orally bioavailable benzothiazole-benzenesulfonamide derivatives as ABCA1 upregulators for the management of dyslipidemia

  • Eur J Med Chem. 2026 Mar 15:306:118582. doi: 10.1016/j.ejmech.2026.118582.
Wenyan Li 1,  Lijuan Lei 2,  Guosheng Zhang 3,  Yunjin Zhang 4,  Yujie Wang 3,  Yexiang Wu 2,  Ren Sheng 2,  Guijun Yang 2,  Yanni Xu 5,  Hongtao Liu 6
Affiliations

Affiliations

  • 1 Hebei Key Laboratory of Organic Functional Molecules, College of Chemistry and Materials Science, Hebei Normal University, Shijiazhuang 050024, China. Electronic address: [email protected].
  • 2 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, NHC Key Laboratory of Microbial Drugs, National Center for New Microbial Drug Screening, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS&PUMC), Tiantan Xili 1#, Beijing, 100050, China.
  • 3 Hebei Key Laboratory of Organic Functional Molecules, College of Chemistry and Materials Science, Hebei Normal University, Shijiazhuang 050024, China.
  • 4 Department of Pharmacy, The First Hospital of Hebei Medical University, Shijiazhuang 050000, China.
  • 5 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, NHC Key Laboratory of Microbial Drugs, National Center for New Microbial Drug Screening, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS&PUMC), Tiantan Xili 1#, Beijing, 100050, China. Electronic address: [email protected].
  • 6 Department of Pharmacy, The First Hospital of Hebei Medical University, Shijiazhuang 050000, China. Electronic address: [email protected].
PMID: 41570728 DOI: 10.1016/j.ejmech.2026.118582
Abstract

ATP-binding cassette transporter A1 (ABCA1), a key regulator of Cholesterol efflux and reverse Cholesterol transport, represents a promising therapeutic target for atherosclerosis. However, small-molecule ABCA1 upregulators combining high potency and drug-like properties remain scarce. Through rational structure optimization, we designed and synthesized a series of novel benzothiazole-benzenesulfonamide derivatives. These compounds were systematically evaluated by ABCA1 upregulating activity test, followed by mRNA and protein expression analysis of ABCA1, murine macrophages Cholesterol efflux experiments, safety assessment, and in vivo efficacy studies in hyperlipidemic golden hamsters and pharmacokinetic (PK) profiling in ICR mice. Several derivatives, particularly compound 85 demonstrated unprecedented ABCA1 upregulating activity (up to 578 %, EC50 = 0.15 μM). Compounds 25, 56, 68, 85 and 87 significantly induced ABCA1 expression at both mRNA and protein levels, promoted Cholesterol efflux in RAW264.7 macrophage cells, and exhibited favorable safety profiles in acute toxicity tests. In hyperlipidemic golden hamsters, these compounds markedly improved plasma lipid profiles-notably increasing HDL-C levels by up to 44 % while effectively reducing TC and TG. Importantly, 85 and 87 displayed exceptional PK properties with oral bioavailability >90 % and systemic exposure significantly superior to conventional lipid-lowering drugs.

Keywords

ABCA1 upregulator; ATP-binding cassette transporter A1 (ABCA1); Atherosclerosis; Benzothiazole-benzenesulfonamide.

Figures
Products