Targeting Carnitine Biosynthesis: Discovery of New Inhibitors against γ-Butyrobetaine Hydroxylase
Journal of Medicinal Chemistry 2014
Kaspars Tārs, Janis Leitans, Andris Kazaks, Diāna Zeļencova-Gopejenko, Edgars Liepiņš, Jānis Kūka, Marina Makrecka, Daina Lola, Viktors Andrianovs, Daina Gustina, Solveiga Grinberga, Edvards Liepiņš, Ivars Kalviņš, Maija Dambrova, Einārs Loža, Osvalds Pugovičs

γ-Butyrobetaine hydroxylase (BBOX) catalyzes the conversion of gamma butyrobetaine (GBB) to l-carnitine, which is involved in the generation of metabolic energy from long-chain fatty acids. BBOX inhibitor 3-(1,1,1-trimethylhydrazin-1-ium-2-yl)propanoate (mildronate), which is an approved, clinically used cardioprotective drug, is a relatively poor BBOX inhibitor and requires high daily doses. In this paper we describe the design, synthesis, and properties of 51 compounds, which include both GBB and mildronate analogues. We have discovered novel BBOX inhibitors with improved IC 50 values; the best examples are in the nanomolar range and about 2 orders of magnitude better when compared to mildronate. For six inhibitors, crystal structures in complex with BBOX have been solved to explain their activities and pave the way for further inhibitor design. © 2014 American Chemical Society.


DOI
10.1021/jm401603e
Hipersaite
http://pubs.acs.org/doi/abs/10.1021/jm401603e

Tārs, K., Leitans, J., Kazaks, A., Zeļencova, D., Liepiņš, E., Kūka, J., Makrecka, M., Lola, D., Andrianovs, V., Gustina, D., Grinberga, S., Liepiņš, E., Kalviņš, I., Dambrova, M., Loža, E., Pugovičs, O. Targeting Carnitine Biosynthesis: Discovery of New Inhibitors against γ-Butyrobetaine Hydroxylase. Journal of Medicinal Chemistry, 2014, Vol.57, Iss.6, 2213.-2236.lpp. ISSN 0022-2623. Pieejams: doi:10.1021/jm401603e

Publikācijas valoda
English (en)
RTU Zinātniskā bibliotēka.
E-pasts: uzzinas@rtu.lv; Tālr: +371 28399196