1415114-05-4Relevant articles and documents
A convergent, scalable and stereoselective synthesis of azole CYP51 inhibitors
Lepesheva, Galina,Christov, Plamen,Sulikowski, Gary A.,Kim, Kwangho
, p. 4248 - 4250 (2017)
The study and development of azole-based CYP51 inhibitors is an active area of research across disciplines of biochemistry, pharmacology and infectious disease. Support of in vitro and in vivo studies require the development of robust asymmetric routes to single enantiomer products of this class of compounds. Herein, we describe a scalable and enantioselective synthesis to VNI and VFV, the two potent inhibitors of protozoan sterol 14α-demethylase (CYP51) that are currently under consideration for clinical trials for Chagas disease. A key transformation is the Jacobsen Hydrolytic Kinetic Resolution (HKR) reaction. The utility of the synthetic route is illustrated by the preparation of >25 g quantities of single enantiomers of VNI and VFV.
Organocatalytic, enantioselective synthesis of VNI: A robust therapeutic development platform for Chagas, a neglected tropical disease
Dobish, Mark C.,Villalta, Fernando,Waterman, Michael R.,Lepesheva, Galina I.,Johnston, Jeffrey N.
supporting information, p. 6322 - 6325 (2013/02/23)
VNI is a potent inhibitor of CYP51 and was recently shown to achieve a parasitological cure of mice infected with T. cruzi in both acute and chronic stages of infection. T. cruzi is the causative parasite of Chagas disease, a neglected tropical disease. The first enantioselective chemical synthesis of VNI (at a materials cost of less than $0.10/mg) is described. Furthermore, the key enantioselective step is performed at the 10 g scale.
