Shenyang Hinewy Pharmaceutical Technology Co., Ltd.

Hyperuricemia and monosodium urate induced nod-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome activation is the major pathogenesis for gouty arthritis, and urate transporter 1 (URAT1) is a proven target for hyperuricemia. In this study, scaffold hopping modification with tranilast led to the identification of HNW005, an NLRP3 inflammasome and URAT1 dual-target inhibitor, which exhibited notable inhibitory potency against NLRP3 inflammasome activation (K_D = 204.6 nM, IC₅₀ = 1.7 μM) and uric acid transmembrane transportation (IC₅₀ = 6.4 μM). Importantly, HNW005 displayed significant in vivo efficacy with respect to anti-inflammatory, analgesic, and uric acid-lowering effects (decreasing rate = 64.8 % at 2 mg/kg). In addition, HNW005 also displayed an acceptable pharmacokinetic profile (F = 41.37 %, t_1/2 = 3.07 h). Collectively, the results showed that developing dual-target inhibitors of NLRP3 inflammasomes and URAT1 is a feasible strategy for the treatment of gouty arthritis, and HNW005 is worthy of further investigation.

To develop effective agents for ischemic stroke, compounds 19 (IC₅₀ = 0.49 μM) and 36b (IC₅₀ = 0.50 μM), as analogues of our previously reported antiplatelet agent HNW001, were identified as potent P2Y₁ receptor antagonists, which were superior to HNW001 and BPTU (IC₅₀ = 4.07 and 2.50 μM, respectively). Notably, these two compounds showed remarkable neuroprotective potency against oxidative stress by upregulating nuclear Nrf2 protein levels in vitro. Additionally, compounds 19 and 36b demonstrated favorable blood-brain barrier penetration potential in rats, and the rat MCAO model showed that they could effectively reduce infarction sizes with ED₅₀ values of 8.39 and 4.60 mg/kg, respectively. Meanwhile, they could remarkably ameliorate neurobehavioral function, brain water content, oxidative parameters, and hippocampal tissue damage following MCAO. Thus, compounds 19 and 36b were promising lead compounds for developing effective agents to treat ischemic stroke.

Proparacaine hydrochloride is an ester-type local anesthetic agent that is extensively used in ophthalmic operations. The process-related impurities of proparacaine hydrochloride were investigated, and seven impurities were detected in the reaction solution of the last step at the level of 0.03-1.08 % by a newly developed HPLC method. Based on the synthetic process and the results of LC-HRMS, the structures of five impurities were proposed as 3-amino-4-propoxybenzoic acid (Imp-A), ethyl 3-amino-4-propoxybenzoate (Imp-B), 2-(ethylamino)ethyl 3-amino-4-propoxybenzoate hydrochloride (Imp-C), 2-(diethylamino)ethyl 3-nitro-4-propoxybenzoate hydrochloride (Imp-F), and 3-nitro-4-propoxybenzoic acid (Imp-G). And the structures were confirmed by synthesis, followed by varieties of spectral and chromatographic analyses. The structures of two impurities with almost same molecular weight in LC-HRMS were elucidated as 2-(diethylamino)ethyl 3-(ethylamino)-4-propoxy-benzoate hydrochloride (Imp-D) and 2-(diethylamino)ethyl 3-formamido-4-propoxybenzoate hydrochloride (Imp-E) by NMR and IR. An HPLC-based method was developed, and validation study demonstrated that the approach was precise, accurate, and sensitive. The impurities information of proparacaine hydrochloride can be used for the quality control of intermediate, raw material drug and its commercial products.