Selective reduction of N-oxides to amines: application to drug metabolism.
Phase I oxidative metabolism of nitrogen-containing drug molecules to their corresponding N-oxides is a common occurrence. There are instances where liquid chromatography/tandem mass spectometry techniques are inadequate to distinguish this pathway from other oxidation processes, including C-hydroxylations and other heteroatom oxidations, such as sulfur to sulfoxide. Therefore, the purpose of the present study was to develop and optimize an efficient and practical chemical method to selectively convert N-oxides to their corresponding amines suitable for drug metabolism applications. Our results indicated that efficient conversion of N-oxides to amines could be achieved with TiCl(3) and poly(methylhydrosiloxane). Among them, we found TiCl(3) to be a facile and easy-to-use reagent, specifically applicable to drug metabolism. There are a few reports describing the use of TiCl(3) to reduce N-O bonds in drug metabolism studies, but this methodology has not been widely used. Our results indicated that TiCl(3) is nearly as efficient when the reductions were carried out in the presence of biological matrices, including plasma and urine. Finally, we have shown a number of examples where TiCl(3) can be successfully used to selectively reduce N-oxides in the presence of sulfoxides and other labile groups.
Kulanthaivel
Palaniappan
P
Drug Disposition, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. pkulanthaivel@lilly.com
Barbuch
Robert J
RJ
Davidson
Rita S
RS
Yi
Ping
P
Rener
Gregory A
GA
Mattiuz
Edward L
EL
Hadden
Chad E
CE
Goodwin
Lawrence A
LA
Ehlhardt
William J
WJ
D000588:Amines / Q000378:metabolism*; D000818:Animals; D002384:Catalysis; D002853:Chromatography, Liquid; D003497:Cyclic N-Oxides / Q000378:metabolism*; D004285:Dogs; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D005663:Furans / Q000737:chemistry / Q000378:metabolism; D006900:Hydroxylation / Q000187:drug effects; D007536:Isomerism; D007546:Isoquinolines / Q000737:chemistry / Q000378:metabolism; D013058:Mass Spectrometry; D015394:Molecular Structure; D010084:Oxidation-Reduction / Q000187:drug effects; D010165:Palladium / Q000737:chemistry; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011724:Pyridazines / Q000378:metabolism; D051381:Rats; D012709:Serum Albumin / Q000737:chemistry / Q000378:metabolism; D012833:Siloxanes / Q000378:metabolism; D013454:Sulfoxides / Q000378:metabolism; D013696:Temperature; D013997:Time Factors; D014025:Titanium / Q000378:metabolism; D014748:Vinca Alkaloids / Q000097:blood / Q000652:urine; D014867:Water
D000588:Amines; D003497:Cyclic N-Oxides; D005663:Furans; D007546:Isoquinolines; D004364:Pharmaceutical Preparations; D011724:Pyridazines; D012709:Serum Albumin; D012833:Siloxanes; D013454:Sulfoxides; D014748:Vinca Alkaloids; C402373:poly(methylhydrosiloxane); D014867:Water; C039296:pleurosine; C018674:tetrahydrofuran; D010165:Palladium; D014025:Titanium; C039460:titanium trichloride