TY - JOUR
T1 - Targeting carnitine biosynthesis
T2 - Discovery of new inhibitors against γ-butyrobetaine hydroxylase
AU - Tars, Kaspars
AU - Leitans, Janis
AU - Kazaks, Andris
AU - Zelencova, Diana
AU - Liepinsh, Edgars
AU - Kuka, Janis
AU - Makrecka, Marina
AU - Lola, Daina
AU - Andrianovs, Viktors
AU - Gustina, Daina
AU - Grinberga, Solveiga
AU - Liepinsh, Edvards
AU - Kalvinsh, Ivars
AU - Dambrova, Maija
AU - Loza, Einars
AU - Pugovics, Osvalds
PY - 2014/3/27
Y1 - 2014/3/27
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84897401258&partnerID=8YFLogxK
U2 - 10.1021/jm401603e
DO - 10.1021/jm401603e
M3 - Article
C2 - 24571165
AN - SCOPUS:84897401258
SN - 0022-2623
VL - 57
SP - 2213
EP - 2236
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 6
ER -