Design and synthesis of pyrrolo[3,2-d]pyrimidine HER2/EGFR dual inhibitors: improvement of the physicochemical and pharmacokinetic profiles for potent in vivo anti-tumor efficacy.

Abstract During the course of our studies on a novel HER2/EGFR dual inhibitor (TAK-285), we found an alternative potent pyrrolo[3,2- d ]pyrimidine compound ( 1a ). To enhance the pharmacokinetic (PK) profile of this compound, we conducted chemical modifications into its N - 5 side chain and conversion of the chemically modified compounds into their salts. Among them, 2cb , the tosylate salt of compound 2c , showed potent HER2/EGFR kinase inhibitory activity (IC 50 : 11/11 nM) and cellular growth inhibitory activity (BT-474 cell GI 50 : 56 nM) with a good drug metabolism and PK (DMPK) profile. Furthermore, 2cb exhibited significant in vivo antitumor efficacy in both mouse and rat xenograft models with transplanted 4-1ST gastric cancer cell lines (mouse, T/C = 0%, 2cb po bid at 100 mg/kg; rat, T/C: -1%, 2cb po bid at 25 mg/kg).