A N-propionylsulfonamide prodrug of K-5a2 provided improved aqueous solubility and hERG inhibition

<title>Abstract</title> Background Having the potential disadvantages and safety risk of the use of anti-HIV-1 drug candidate <bold>K-5a2</bold> in the longterm treatment of HIV patients in mind, we set out with the goal of finding a second-generation backup compound of <bold>K-5a2</bold> with the appropriate anti-HIV potency, significantly reduced hERG activity, decreased induction of the CYP enzyme, and improved aqueous solubility. Herein, using a N-propionylsulfonamide prodrug strategy, we report the discovery of compound <bold>HM-1</bold>Methods In vitro assay of anti-HIV activities in TZM-bl and MT-4 cells, metabolic stability in HLM and human plasma, measurements of water solubility and Log P, assay procedures for hERG activity, acute and subacute toxicity experiment and cytochrome P450 inhibition assay were carried out for <bold>HM-1</bold>.Results <bold>HM-1</bold> can be rapidly hydrolyzed to parent drug <bold>K-5a2</bold> and exhibited high potency against HIV-1_{NL4 − 3} strain (EC₅₀ = 7.99 nM) in TZM-bl cells, HIV-1_IIIB strain (EC₅₀ = 2.9 nM) and HIV-1_Y181C strain (EC₅₀ = 5.5 nM) in MT-4 cells. And it also showed a &gt; 70-fold improvement in aqueous solubility and presented a low acute toxicity in mice (LD₅₀ &gt; 2 g•kg^{− 1}); no obvious organ damage was detected in the assessment of subacute toxicity. Meanwhile, <bold>HM-1</bold> also showed 50 times lower hERG inhibition (IC₅₀ = 6.39 µM) than <bold>K-5a2</bold> (IC₅₀ = 0.13 µM).Conclusions It was <bold>HM-1</bold> appeared to be free of most of the drawbacks associated with <bold>K-5a2</bold> and has been selected for further development as an oral anti-HIV-infection agent.