Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 2 de 2
Filter
Add more filters










Database
Language
Publication year range
1.
J Med Chem ; 60(13): 5663-5672, 2017 07 13.
Article in English | MEDLINE | ID: mdl-28594552

ABSTRACT

Herein we describe the identification of 4-{[1,2,4]triazolo[1,5-a]pyridin-5-yl}benzonitrile-based inhibitors of the hypoxia-inducible factor prolylhydroxylase domain-1 (PHD-1) enzyme. These inhibitors were shown to possess a novel binding mode by X-ray crystallography, in which the triazolo N1 atom coordinates in a hitherto unreported monodentate interaction with the active site Fe2+ ion, while the benzonitrile group accepts a hydrogen-bonding interaction from the side chain residue of Asn315. Further optimization led to potent PHD-1 inhibitors with good physicochemical and pharmacokinetic properties.


Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Hypoxia-Inducible Factor-Proline Dioxygenases/antagonists & inhibitors , Pyridines/chemistry , Pyridines/pharmacology , Triazoles/chemistry , Triazoles/pharmacology , Animals , Crystallography, X-Ray , Dogs , Enzyme Inhibitors/pharmacokinetics , Humans , Hypoxia-Inducible Factor-Proline Dioxygenases/chemistry , Hypoxia-Inducible Factor-Proline Dioxygenases/metabolism , Madin Darby Canine Kidney Cells , Mice , Mice, Inbred C57BL , Molecular Docking Simulation , Pyridines/pharmacokinetics , Triazoles/pharmacokinetics
2.
J Am Chem Soc ; 132(39): 13922-7, 2010 Oct 06.
Article in English | MEDLINE | ID: mdl-20843035

ABSTRACT

A systematic study of the asymmetric deprotonation of a dimethyl-substituted phosphine sulfide using organolithium bases in the presence of (-)-sparteine has been carried out. Use of nBuLi and (-)-sparteine in Et(2)O at -78 °C gave trapped adducts in ∼88:12 er via a kinetically controlled process that was successfully predicted using a computational approach at the B3LYP/6-31+G(d) level. This initial kinetic enantioselectivity could be enhanced up to 97:3 er by trapping the lithiated intermediate with a prochiral electrophile (e.g., pivaldehyde or tBuPCl(2)). In addition, it was found that the R(P) and S(P) stereoisomers of the lithiated methylphosphine sulfide could interconvert at temperatures above 0 °C. Such interconversion is unprecedented and differs from the configurational instability of organolithiums that are stereogenic at a lithiated carbon atom. The major, thermodynamically preferred diastereomeric (-)-sparteine-complexed lithated phosphine sulfide was investigated by X-ray crystallography and computational methods at the B3LYP/6-31+G(d) level. Through the interconversion of the R(P) and S(P) stereoisomers of the lithiated methylphosphine sulfide, a novel dynamic thermodynamic resolution of a racemic lithiated phosphine sulfide has been developed. Thus, the phosphine sulfide was lithiated with nBuLi, and then (-)-sparteine was added. After equilibration at 0 °C for 3 h, electrophilic trapping generated an adduct in 81:19 er with the configuration opposite to that obtained under kinetic control. Thus, the methodology provides access to P-stereogenic compounds with the opposite sense of induction using (-)-sparteine as the ligand simply by changing the reaction conditions (kinetic or thermodynamic control).


Subject(s)
Phosphines/chemical synthesis , Sparteine/chemistry , Sulfides/chemical synthesis , Thermodynamics , Crystallography, X-Ray , Kinetics , Lithium/chemistry , Models, Molecular , Molecular Conformation , Molecular Dynamics Simulation , Organometallic Compounds/chemistry , Phosphines/chemistry , Stereoisomerism , Sulfides/chemistry
SELECTION OF CITATIONS
SEARCH DETAIL
...