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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.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Aoki T,Hyohdoh I,Furuichi N,Ozawa S,Watanabe F,Matsushita M,Sakaitani M,Ori K,Takanashi K,Harada N,Tomii Y,Tabo M,Yoshinari K,Aoki Y,Shimma N,Iikura H

doi

10.1016/j.bmcl.2013.10.001

subject

Has Abstract

pub_date

2013-12-01 00:00:00

pages

6223-7

issue

23

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(13)01185-2

journal_volume

23

pub_type

杂志文章

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