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Optimization of allosteric MEK inhibitors. Part 2: Taming the sulfamide group balances compound distribution properties.

Abstract：

:Recently, we had identified an unexplored pocket adjacent to the known binding site of allosteric MEK inhibitors which allowed us to design highly potent and in vivo efficacious novel inhibitors. We now report that our initial preclinical candidate, featuring a phenoxy side chain with a sulfamide capping group, displayed human carbonic anhydrase off-target activity and species-dependent blood cell accumulation, which prevented us from advancing this candidate further. Since this sulfamide MEK inhibitor displayed an exceptionally favorable PK profile with low brain penetration potential despite being highly oral bioavailable, we elected to keep the sulfamide capping group intact while taming its unwanted off-target activity by optimizing the structural surroundings. Introduction of a neighboring fluorine atom or installation of a methylene linker reduced hCA potency sufficiently, at the cost of MEK target potency. Switching to a higher fluorinated central core reinstated high MEK potency, leading to two new preclinical candidates with long half-lives, high bioavailabilities, low brain penetration potential and convincing efficacy in a K-Ras-mutated A549 xenograft model.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Hartung IV,Hammer S,Hitchcock M,Neuhaus R,Scholz A,Siemeister G,Bohlmann R,Hillig RC,Pühler F

doi

10.1016/j.bmcl.2015.11.004

subject

Has Abstract

pub_date

2016-01-01 00:00:00

pages

186-93

issue

1

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(15)30213-4

journal_volume

26

pub_type

杂志文章

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