The sulfamide moiety affords higher inhibitory activity and oral bioavailability to a series of coumarin dual selective RAF/MEK inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 23; pp. 6223 - 6227
• Main Authors: Aoki, Toshihiro, Hyohdoh, Ikumi, Furuichi, Noriyuki, Ozawa, Sawako, Watanabe, Fumio, Matsushita, Masayuki, Sakaitani, Masahiro, Ori, Kazutomo, Takanashi, Kenji, Harada, Naoki, Tomii, Yasushi, Tabo, Mitsuyasu, Yoshinari, Kiyoshi, Aoki, Yuko, Shimma, Nobuo, Iikura, Hitoshi
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.12.2013; Elsevier
• Subjects: Ames test; Amides - chemistry; Amides - pharmacokinetics; Amides - pharmacology; Animals; Anticancer; bioavailability; Biological Availability; cell growth; Chemistry; Chemistry, Medicinal; Chemistry, Organic; coumarin; Coumarins - chemistry; Coumarins - pharmacokinetics; Coumarins - pharmacology; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; Extracellular Signal-Regulated MAP Kinases - metabolism; growth retardation; Haplorhini; Kinase inhibitor; Life Sciences & Biomedicine; MEK; Mice; Pharmacology & Pharmacy; Physical Sciences; Protein Kinase Inhibitors - pharmacology; Raf; raf Kinases - antagonists & inhibitors; raf Kinases - metabolism; Rats; Science & Technology; Structure-Activity Relationship; Sulfamide; Sulfonic Acids - chemistry; Sulfonic Acids - pharmacokinetics; Sulfonic Acids - pharmacology; Xenograft Model Antitumor Assays; Sulfamide; hERG; MEK; PEG; Raf; TGI; HPCD; LYSA; PAMPA; Anticancer; Kinase inhibitor; ERK; RAS; KINASE; REACTIVITY; DERIVATIVES; CANCER-THERAPY; DISCOVERY; 2-hydroxypropyl-β-cyclodextrin; parallel artificial membrane permeability assay; polyethylene glycol; extracellular signal-regulated kinase; human ether-a-go-go related gene; mitogen-activated protein kinase; lyophilized solubility assay; tumor growth inhibition
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.10.001

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=8nM) and good PK profile (bioavailability of 51% in mouse), resulting in high in vivo antitumor efficacy in the HCT116 xenograft (ED50=4.8mg/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