Importance of the Azole Moiety of Cimetidine Derivatives for the Inhibition of Human Multidrug and Toxin Extrusion Transporter 1 (hMATE1)

Abstract

Herein, we describe the design and synthesis of cimetidine analogs, as well as their inhibitory activity toward the human multidrug and toxin extrusion transporter 1 (hMATE1), which is related to nephrotoxicity of drugs. Cimetidine is the histamine H 2 -receptor antagonist, but also inhibits hMATE1, which is known to cause renal impairment. We designed and synthesized cimetidine analogs to evaluate hMATE1 inhibitory activity to reveal whether the analogs could reduce the inhibition of hMATE1. The results showed that all analogs with an unsubstituted guanidino group exhibited hMATE1 inhibitory activity. On the other hand, there was a clear difference in the hMATE1 inhibitory activity for the other compounds. That is, compounds with a methylimidazole ring exhibited hMATE1 inhibition, while compounds with a phenyl ring did not. The results suggest that the ability to form hydrogen bonds at the azole moiety is strongly involved in the hMATE1 inhibition.

Prediction of Inhibitory Activity Against the MATE1 Transporter via Combined Fingerprint- and Physics-Based Machine Learning Models

“…The NH moiety of the azole formed a hydrogen bond with Glu389, the azole ring can also form a π-interaction with Tyr299, and the cyanoguanidine moiety formed a hydrogen bond with Gln49. The interactions with Glu389 and Tyr299 were consistent with the previous report; and although the interaction with Gln49 was not reported, the position of the compound was consistent with the previous study 50 . Hence we concluded that the quality of our docking poses passed this plausibility check by comparison with a previous study.…”