Trimethylsilylpyrazoles as novel inhibitors of p38 MAP kinase: A new use of silicon bioisosteres in medicinal chemistry

Importance of Silicon Atom in the Drug Design Process

“…Silicon containing compounds have been recently synthesized as carbon isostere and evaluated for their biological activities. It has been reported that the t-Bu group of the p38 MAPK inhibitors (BIRB-796) was replaced by trimethylsilyl and this compound is as equipotent as BIRB-796 [2] . Fig.…”

“…2. p38 MAPK inhibitor BIRB-796 and its silicon derivatives (SiBIRB-796) [2] . successfully used in nuclear receptor, vanilloid receptor (VR1) [23][24][25] .…”

“…Silicon substitution of carbon in existing drug is attractive strategy to search for new drug like candidate with favorable biological properties. In the literature there have been number of silicon containing inhibitors are reported with the different synthesis strategy against different targets [2][3][4][5] . Silicon containing organic molecules such as silanols, silandiols, and silyl fluoride are particularly interesting to chemists, because of their different biochemical properties compared to their carbon containing isosteres.…”

Molecular Variations Based on Isosteric Replacements

“…The application of this isosterism remains, however, limited. Figure 8.68 shows a silicon-containing hypocholesterolemic squalene epoxidase inhibitor; [228,229] the silicon analog of the α 2 -adrenergic antagonist atipamezole; [230] a highly potent, stable, and CNS-penetrating silatecan; [231] some ACE inhibitors; [232] HIV protease inhibitors; [233] the (R)-sila-analog of the antidepressant venlafaxine; [234] and a trimethylsilylpyrazole as novel inhibitor of p38 MAP kinase [235] (mitogen-activating protein). Silicon is more electropositive than carbon (and even more if compared to oxygen and nitrogen) and the covalent siliconÀcarbon bonds in the sp 3 hybridization state are 20 percent longer than the corresponding carbonÀcarbon bond.…”

Exploring Organosilane Amines as Potent Inhibitors and Structural Probes of Influenza A Virus M2 Proton Channel

“…17, 18 The most common carbon to silicon switch strategies fall into one of the two classes (Scheme 1). In the first class, a quaternary carbon is replaced with a silicon to increase hydrophobicity 19 (Scheme 1 a). In the second class, a carbonyl is replaced with a sterically hindered silanediol to mimic the high-energy intermediate of an amide bound hydrolysis, provides opportunities to inhibit proteins such as proteases 20 (Scheme 1 b).…”