Organic Chemistry: Current Research
Open Access

Synthesis of ALK5 kinase inhibitors based on substituted homoallenyl aldehyde

10^th European Organic Chemistry Congress

March 21-22, 2019 | Rome, Italy

Milan Potacek, Lukas Tenora and Juraj Galeta

Masaryk University, Czech Republic

Posters & Accepted Abstracts: Organic Chem Curr Res

Abstract :

ALK5 (Activin-like kinase-5) plays important roles in many pathological states including inflammation, fibrosis, cancer, asthma and cardiovascular diseases.1-3 Various low molecular weight inhibitors of ALK5 containing different substituted heterocyclic skeletons like imidazole, pyrazole, pyrrolo[1,2-b]pyrazole and pteridine were synthesized and published.4-5 Our recent work is focused on synthesis of new inhibitors of ALK5 kinases.6-7 We synthesized a series of 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles with various substitution at positions 2, 3 and 4.The most active compound in the set of almost 40 final products showed IC50 = 80 nM for ALK5. The selectivity for ALK5 in a panel of 50 protein kinases, as well as some experiments in cells (dephosphorylation of SMADF2, translocation of SMAD2/3 to nuclei) are discussed. In the literature one can find several ways for the formation of 5,6-dihydro-4H-pyrrolo[1,2-b] pyrazole ring but their synthesis is often complicated and has not always good yield.8-9 Our experience in application of homoallenyl aldehyde enabled us to find an easier route to those fused heterocyclic compounds. Our approach is depicted at Figure 1.

Biography :

Milan Potá�?ek is working in heterocyclic chemistry in the field of pericyclic reactions, their regio and stereoselectivity, especially on 1,3-dipolar cycloadditions and their new intramolecular variation - “criss-cross” cycloadditions with application of allene synthone as a dipolarophile. Following their applications lead to many various products otherwise difficult to preparation. Here presented work was carried out by his doctoral students.