1297594-71-8Relevant academic research and scientific papers
Optimization of allosteric MEK inhibitors. Part 1: Venturing into underexplored SAR territories
Hartung, Ingo V.,Hitchcock, Marion,Pühler, Florian,Neuhaus, Roland,Scholz, Arne,Hammer, Stefanie,Petersen, Kirstin,Siemeister, Gerhard,Brittain, Dominic,Hillig, Roman C.
, p. 2384 - 2390 (2013)
Using PD325901 as a starting point for identifying novel allosteric MEK inhibitors with high cell potency and long-lasting target inhibition in vivo, truncation of its hydroxamic ester headgroup was combined with incorporation of alkyl and aryl ethers at the neighboring ring position. Whereas alkoxy side chains did not yield sufficient levels of cell potency, specifically substituted aryloxy groups allowed for high enzymatic and cellular potencies. Sulfamide 28 was identified as a highly potent MEK inhibitor with nanomolar cell potency against B-RAF (V600E) as well as Ras-mutated cell lines, high metabolic stability and resulting long half-lives. It was efficacious against B-RAF as well as K-Ras driven xenograft models and showed - despite being orally bioavailable and not a P-glycoprotein substrate - much lower brain/plasma exposure ratios than PD325901.
Optimization of allosteric MEK inhibitors. Part 2: Taming the sulfamide group balances compound distribution properties
Hartung, Ingo V.,Hammer, Stefanie,Hitchcock, Marion,Neuhaus, Roland,Scholz, Arne,Siemeister, Gerhard,Bohlmann, Rolf,Hillig, Roman C.,Pühler, Florian
, p. 186 - 193 (2015/12/23)
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.
