RTU Research Information System
Latviešu English

Publikācija: Targeting Carnitine Biosynthesis: Discovery of New Inhibitors against γ-Butyrobetaine Hydroxylase

Publication Type Scientific article indexed in SCOPUS or WOS database
Funding for basic activity Unknown
Defending: ,
Publication language English (en)
Title in original language Targeting Carnitine Biosynthesis: Discovery of New Inhibitors against γ-Butyrobetaine Hydroxylase
Field of research 1. Natural sciences
Sub-field of research 1.4 Chemical sciences
Authors Kaspars Tārs
Janis Leitans
Andris Kazaks
Diāna Zeļencova
Edgars Liepiņš
Jānis Kūka
Marina Makrecka
Daina Lola
Viktors Andrianovs
Daina Gustina
Solveiga Grinberga
Edvards Liepiņš
Ivars Kalviņš
Maija Dambrova
Einārs Loža
Osvalds Pugovičs
Keywords
Abstract 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
Hyperlink: http://pubs.acs.org/doi/abs/10.1021/jm401603e 
Reference 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, pp.2213-2236. ISSN 0022-2623. Available from: doi:10.1021/jm401603e
Additional information Citation count:
ID 24099