Amelioration of mechanism-based inactivation of CYP3A4 by a H-PGDS inhibitor.

•One of the leads in a H-PGDS inhibition program showed MBI of CYP3A4.•Metabolite IDs of the compound and analogs were collected.•Docking of the compounds into a modified CYP3A4 structure afforded productive poses.•3-methyl indole, a substructure, from the compound is known to form reactive metabolites.•All of the above was used to rationally design MBI-free H-PGDS compounds.