Discovery of 1-(4-((3-(4-methylpiperazin-1-yl)propyl)amino)benzyl)-5-(trifluoromethyl)pyridin-2(1H)-one, an orally active multi-target agent for the treatment of diabetic nephropathy

Chen, Jun; Peng, Zhangzhe; Lu, Miaomiao; Xiong, Xuan; Chen, Zhuo; Li, Qianbin; Zhang, Cheng; Jiang, Dejian; Tao, Ling; Hu, Gaoyun

doi:10.1016/j.bmcl.2017.07.001

Cited by 8 publications

(3 citation statements)

References 37 publications

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“…In contrast, mefunidone exhibited lower toxicity (Han et al, 2021;Jiang et al, 2021). 3) Mefunidone showed better anti-fibrosis and antiinflammatory effects in unilateral urethral obstruction (UUO) animal models and several cell lines (Liu et al, 2015;Chen et al, 2018). The anti-fibrotic effect of mefunidone was estimated to be 20fold stronger than that of pirfenidone (Liu et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

A phase I, randomized study to evaluate the safety, tolerability, and pharmacokinetics of mefunidone in healthy subjects

Han,

Huo,

et al. 2024

Front. Pharmacol.

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BackgroundMefunidone is a novel synthetic compound and is better when compared to pirfenidone for the anti-fibrotic treatment of renal fibrosis in end-stage renal disease. We conducted this first-in-human, phase I clinical trial to determine the safety, tolerability, and pharmacokinetic (PK) (including food effect) profiles of mefunidone administered orally as single and multiple ascending doses in healthy subjects.MethodsPart A assessed single ascending doses of mefunidone from 25 mg to 800 mg or placebo once daily in the fasting state. Part A also assessed the effect of food on tolerability and PK in the 100 mg cohort. Part B consisted of three treatment groups who received 100 mg, 200 mg, or 400 mg of mefunidone or placebo twice daily (BID, bis in die) on days 1–6 and once in the morning on day 7.ResultsSingle oral doses of mefunidone up to 800 mg and multiple doses of mefunidone up to 400 mg BID were all well-tolerated. Mefunidone behaved with ideal dose proportionality within the single-dose range of 50 mg–600 mg and the multiple-dose range of 100 mg BID to 400 mg BID by day 7. High-fat fed conditions led to a delay in Tmax by approximately 1 h and a slight reduction of approximately 20% in Cmax compared to that in fasting conditions, but it did not significantly affect systemic exposure.ConclusionMefunidone exhibited favorable pharmacokinetics and safety profiles. The present study informed and supported further developmental clinical studies of mefunidone.Clinical Trial Registrationclinicaltrials.gov, identifier CXHL1900206

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Section: Introductionmentioning

confidence: 99%

A phase I, randomized study to evaluate the safety, tolerability, and pharmacokinetics of mefunidone in healthy subjects

Han,

Huo,

et al. 2024

Front. Pharmacol.

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“…In 2012, Hu et al reported the synthesis and evaluation of 5-substituent of 2(1 H )-pyridone derivatives as anti-fibrosis agents; very good in vitro activity was obtained compared to pirfenidone. 21 Inspired by the novel scaffold and hope to improve its poor water-solubility and high toxicity, 22 herein, we disclose our preliminary study of new pirfenidone derivatives as anti-fibrosis agents.…”

Section: Introductionmentioning

confidence: 99%