title: Targeting carnitine biosynthesis: discovery of new inhibitors against γ-butyrobetaine hydroxylase.
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 IC50 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.
authors.affiliation: Biomedical Research and Study Centre , Ratsupites 1, LV1067 Riga, Latvia.
authors.forename: Kaspars
authors.initials: K
authors.lastname: Tars
authors.forename: Janis
authors.initials: J
authors.lastname: Leitans
authors.forename: Andris
authors.initials: A
authors.lastname: Kazaks
authors.forename: Diana
authors.initials: D
authors.lastname: Zelencova
authors.forename: Edgars
authors.initials: E
authors.lastname: Liepinsh
authors.forename: Janis
authors.initials: J
authors.lastname: Kuka
authors.forename: Marina
authors.initials: M
authors.lastname: Makrecka
authors.forename: Daina
authors.initials: D
authors.lastname: Lola
authors.forename: Viktors
authors.initials: V
authors.lastname: Andrianovs
authors.forename: Daina
authors.initials: D
authors.lastname: Gustina
authors.forename: Solveiga
authors.initials: S
authors.lastname: Grinberga
authors.forename: Edvards
authors.initials: E
authors.lastname: Liepinsh
authors.forename: Ivars
authors.initials: I
authors.lastname: Kalvinsh
authors.forename: Maija
authors.initials: M
authors.lastname: Dambrova
authors.forename: Einars
authors.initials: E
authors.lastname: Loza
authors.forename: Osvalds
authors.initials: O
authors.lastname: Pugovics
mesh_terms: D002151:Calorimetry; D002331:Carnitine / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D007202:Indicators and Reagents; D007700:Kinetics; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008763:Methylhydrazines / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry; D013329:Structure-Activity Relationship; D050563:gamma-Butyrobetaine Dioxygenase / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D008024:Ligands; D008763:Methylhydrazines; D011994:Recombinant Proteins; C050147:3-(2,2,2-trimethylhydrazine)propionate; D050563:gamma-Butyrobetaine Dioxygenase; D002331:Carnitine