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

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.