BACKGROUND: UR-13756 is a potent and selective p38 mitogen-activated protein kinase (MAPK) inhibitor, reported to have good bioavailability and pharmacokinetic properties and, thus, is of potential use in the treatment of accelerated aging in Werner syndrome. RESULTS AND DISCUSSION: Irradiation of 2-chloroacrylonitrile and methylhydrazine in ethanol at 100 °C gives 1-methyl-3-aminopyrazole, which reacts with 4-fluorobenzaldehyde and a ketone, obtained by Claisen condensation of 4-picoline, in a Hantzsch-type 3-component hereocyclocondensation, to give the pyrazolopyridine UR-13756. UR-13756 shows p38 MAPK inhibitory activity in human telomerase reverse transcriptase-immortalized HCA2 dermal fibroblasts, with an IC(50) of 80 nm, as shown by ELISA, is 100% efficacious for up to 24 h at 1.0 μm and displays excellent kinase selectivity over the related stress-activated c-Jun kinases. In addition, UR-13756 is an effective p38 inhibitor at 1.0 μm in Werner syndrome cells, as shown by immunoblot. CONCLUSION: The convergent synthesis of UR-13756 is realized using microwave dielectric heating and provides a highly selective inhibitor that shows excellent selectivity for p38 MAPK over c-Jun N-terminal kinase.
BACKGROUND: UR-13756 is a potent and selective p38 mitogen-activated protein kinase (MAPK) inhibitor, reported to have good bioavailability and pharmacokinetic properties and, thus, is of potential use in the treatment of accelerated aging in Werner syndrome. RESULTS AND DISCUSSION: Irradiation of 2-chloroacrylonitrile and methylhydrazine in ethanol at 100 °C gives 1-methyl-3-aminopyrazole, which reacts with 4-fluorobenzaldehyde and a ketone, obtained by Claisen condensation of 4-picoline, in a Hantzsch-type 3-component hereocyclocondensation, to give the pyrazolopyridine UR-13756. UR-13756 shows p38 MAPK inhibitory activity in human telomerase reverse transcriptase-immortalized HCA2 dermal fibroblasts, with an IC(50) of 80 nm, as shown by ELISA, is 100% efficacious for up to 24 h at 1.0 μm and displays excellent kinase selectivity over the related stress-activated c-Jun kinases. In addition, UR-13756 is an effective p38 inhibitor at 1.0 μm in Werner syndrome cells, as shown by immunoblot. CONCLUSION: The convergent synthesis of UR-13756 is realized using microwave dielectric heating and provides a highly selective inhibitor that shows excellent selectivity for p38 MAPK over c-Jun N-terminal kinase.
Authors: Terence Davis; Matthew C Dix; Michal J Rokicki; Amy Jc Brook; Caroline S Widdowson; David Kipling; Mark C Bagley Journal: Chem Cent J Date: 2011-12-08 Impact factor: 4.215
Authors: Mark C Bagley; Mohammed Baashen; Irina Chuckowree; Jessica E Dwyer; David Kipling; Terence Davis Journal: Pharmaceuticals (Basel) Date: 2015-06-03
Authors: Hannah S E Tivey; Michal J Rokicki; James R Barnacle; Matthew J Rogers; Mark C Bagley; David Kipling; Terence Davis Journal: J Gerontol A Biol Sci Med Sci Date: 2013-02-11 Impact factor: 6.053
Authors: Dauren Alimbetov; Terence Davis; Amy J C Brook; Lynne S Cox; Richard G A Faragher; Talgat Nurgozhin; Zhaxybay Zhumadilov; David Kipling Journal: Biogerontology Date: 2015-09-23 Impact factor: 4.277