Drug Metabolism in Drug Design and Development Basic Concepts and Practice

TABLE 12.11 (

Continued

)

Metabolic reaction

Metabolite identification examples

NMR indications

Confirmation method

and comments

11. Hydrolysis

NH

N

O

O

O

O

OH

NH

N

HO

O

O

O

OH

Enalaprilate

Enalapril

The ethylene protons

(d

4.5, q, 2H;

d1.2, t, 3H)

disappeared from theproton spectrum of theEnalaprilate and the restof the protons and the spinsystem were intact

There is no need for

confirmation

12.Glucuronide

conjugation(Froehlich et al.,2005)

N

N

NH

2

HO

N

N

NH

2

O

O

HOOCHOHO

HO

N

HN

N

O

HOOCHOHO

HO

OH

N-h

ydrox

ydebriso

quenine

The O versus

N-glucuronidation wasnot determined from theproton spectrum as theanomeric protons forboth of the regio isomerswere in the 4.5–6 ppmrange.

However, measurement of

anomeric carbon chemicalshifts provided the answerdue to significant chemicalshift differences between theO-glucoronide (100–110 ppm)and the N-glucoronide(80–90 ppm).

(Zhang et al.,

2004)

HN

FC^3

O

FO

Cl

N

FC^3

O

FO

Cl

N

FC^3

O

FO

Cl

O

O OH

OH

HO

HO

O

O OH

OH

HO

HO

or

BMS-204352

Confirmed

The carbon chemical shift

(d

82.9 ppm) for the

anomeric carbon C1

0

was

indicated from the HMQCexperiment, which isconsistent with theN-conjugation

The N-glucuronide structure

was confirmed by the HMBCexperiment. Observationof the long range H



C

correlation from the anomericproton to the indolinonecarbonyl supported theN

-glucuronide conjugation

402