title: The sulfamide moiety affords higher inhibitory activity and oral bioavailability to a series of coumarin dual selective RAF/MEK inhibitors.
abstract: Introducing a sulfamide moiety to our coumarin derivatives afforded enhanced Raf/MEK inhibitory activity concomitantly with an acceptable PK profile. Novel sulfamide 17 showed potent HCT116 cell growth inhibition (IC50=8 nM) and good PK profile (bioavailability of 51% in mouse), resulting in high in vivo antitumor efficacy in the HCT116 xenograft (ED50=4.8 mg/kg). We confirmed the sulfamide moiety showed no negative impact on tests run on the compound to evaluate DMPK (PK profiles in three animal species, CYP inhibition and CYP induction) and the safety profile (hERG and AMES tests). Sulfamide 17 had favorable properties that warranted further preclinical assessment.
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Aoki
authors.forename: Ikumi
authors.initials: I
authors.lastname: Hyohdoh
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Furuichi
authors.forename: Sawako
authors.initials: S
authors.lastname: Ozawa
authors.forename: Fumio
authors.initials: F
authors.lastname: Watanabe
authors.forename: Masayuki
authors.initials: M
authors.lastname: Matsushita
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sakaitani
authors.forename: Kazutomo
authors.initials: K
authors.lastname: Ori
authors.forename: Kenji
authors.initials: K
authors.lastname: Takanashi
authors.forename: Naoki
authors.initials: N
authors.lastname: Harada
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Tomii
authors.forename: Mitsuyasu
authors.initials: M
authors.lastname: Tabo
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yoshinari
authors.forename: Yuko
authors.initials: Y
authors.lastname: Aoki
authors.forename: Nobuo
authors.initials: N
authors.lastname: Shimma
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Iikura
mesh_terms: D000577:Amides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D003374:Coumarins / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000882:Haplorhini; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013451:Sulfonic Acids / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D048490:raf Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000577:Amides; D003374:Coumarins; D047428:Protein Kinase Inhibitors; D013451:Sulfonic Acids; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: 2-hydroxypropyl-β-cyclodextrin; Anticancer; ERK; HPCD; Kinase inhibitor; LYSA; MEK; PAMPA; PEG; Raf; Sulfamide; TGI; extracellular signal-regulated kinase; hERG; human ether-a-go-go related gene; lyophilized solubility assay; mitogen-activated protein kinase; parallel artificial membrane permeability assay; polyethylene glycol; tumor growth inhibition