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

Youichi Kawakita; Kazuhiro Miwa; Masaki Seto; Hiroshi Banno; Yoshikazu Ohta; Toshiya Tamura; Tadashi Yusa; Hiroshi Miki; Hidenori Kamiguchi; Yukihiro Ikeda; Toshimasa Tanaka; Keiji Kamiyama; Tomoyasu Ishikawa

doi:10.1016/j.bmc.2012.08.002

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

Bioorg Med Chem. 2012 Oct 15;20(20):6171-80. doi: 10.1016/j.bmc.2012.08.002. Epub 2012 Aug 25.

Authors

Youichi Kawakita¹, Kazuhiro Miwa, Masaki Seto, Hiroshi Banno, Yoshikazu Ohta, Toshiya Tamura, Tadashi Yusa, Hiroshi Miki, Hidenori Kamiguchi, Yukihiro Ikeda, Toshimasa Tanaka, Keiji Kamiyama, Tomoyasu Ishikawa

Affiliation

¹ Pharmaceutical Research Division, Takeda Pharmaceutical Co. Ltd, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. youichi.kawakita@takeda.com

PMID: 22980219
DOI: 10.1016/j.bmc.2012.08.002

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).

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / therapeutic use
Cell Line, Tumor
Drug Design*
ErbB Receptors / antagonists & inhibitors*
ErbB Receptors / metabolism
Half-Life
Humans
Mice
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / therapeutic use
Pyrimidines / chemical synthesis*
Pyrimidines / chemistry*
Pyrimidines / pharmacokinetics
Pyrimidines / therapeutic use
Pyrroles / chemistry*
Pyrroles / pharmacokinetics
Pyrroles / therapeutic use
Rats
Receptor, ErbB-2 / antagonists & inhibitors*
Receptor, ErbB-2 / metabolism
Stomach Neoplasms / drug therapy
Sulfones / chemical synthesis*
Sulfones / chemistry
Sulfones / pharmacokinetics
Transplantation, Heterologous

Substances

Antineoplastic Agents
N-(2-(4-((3-chloro-4-(3-chlorophenoxy)phenyl)amino)-5H-pyrrolo(3,2-d)pyrimidin-5-yl)ethyl)-2-methyl-2-(methylsulfonyl)propanamide
Protein Kinase Inhibitors
Pyrimidines
Pyrroles
Sulfones
pyrrolopyrimidine
ErbB Receptors
Receptor, ErbB-2