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Bioorg Med Chem Lett. 2016 Jan 1;26(1):186-93. doi: 10.1016/j.bmcl.2015.11.004. Epub 2015 Nov 3.

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

Author information

1
Medicinal Chemistry, Bayer HealthCare AG, Global Drug Discovery, Muellerstraße 178, 13353 Berlin, Germany. Electronic address: ingo.hartung@bayer.com.
2
Therapeutic Research Group Oncology, Bayer HealthCare AG, 13353 Berlin, Germany.
3
Medicinal Chemistry, Bayer HealthCare AG, Global Drug Discovery, Muellerstraße 178, 13353 Berlin, Germany.
4
Research Pharmacokinetics, Bayer HealthCare AG, 13353 Berlin, Germany.
5
Structural Biology, Bayer HealthCare AG, 13353 Berlin, Germany.

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.

KEYWORDS:

Allosteric MEK inhibitor; Blood–plasma ratio; Human carbonic anhydrase; Oncology; Structure-based drug design

PMID:
26611920
DOI:
10.1016/j.bmcl.2015.11.004
[Indexed for MEDLINE]

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