title: 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).
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co. Ltd, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. youichi.kawakita@takeda.com
authors.forename: Youichi
authors.initials: Y
authors.lastname: Kawakita
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Miwa
authors.forename: Masaki
authors.initials: M
authors.lastname: Seto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Banno
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Ohta
authors.forename: Toshiya
authors.initials: T
authors.lastname: Tamura
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yusa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miki
authors.forename: Hidenori
authors.initials: H
authors.lastname: Kamiguchi
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Tanaka
authors.forename: Keiji
authors.initials: K
authors.lastname: Kamiyama
authors.forename: Tomoyasu
authors.initials: T
authors.lastname: Ishikawa
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D045744:Cell Line, Tumor; D015195:Drug Design; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011758:Pyrroles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013274:Stomach Neoplasms / Q000188:drug therapy; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D018719:Erb-b2 Receptor Tyrosine Kinases; D013450:Sulfones; C578266:N-(2-(4-((3-chloro-4-(3-chlorophenoxy)phenyl)amino)-5H-pyrrolo(3,2-d)pyrimidin-5-yl)ethyl)-2-methyl-2-(methylsulfonyl)propanamide; C527741:pyrrolopyrimidine