Identification of Degradation Products in the Phosphodiesterase (PDE-4) Inhibitor Roflumilast Using High Resolution Mass Spectrometry and Density Functional Theory Calculations

Saroj Kumar Paul,Upendra N Dash

doi:10.5478/msl.2015.6.2.38

Abstract

Roflumilast analogs are a group of drugs which act as selective photodiesterase (PDE-4) inhibitor for the treatment severe chronic pulmonary disease associated with chronic brochnonities. Structural identification of degradation products using high resolu- tion mass spectrometry and theoretical investigation by density functional theory have been successfully carried out on roflumilast to identify four degradation products namely, 3,5-dichloropyridin-4-amine, N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-hydroxy benzamide, N-(3,5-dichloropyridin-4-yl)-3-(cyclopropylmethoxy)-4-(difluoromethoxy) benzamide and 3-(cyclopropylmethoxy)-N- (3,5-dichloro-1-oxidopyridin-4-yl)-4-(difluoro methoxy) benzamide, generated in alkali, acidic and oxidative conditions.

Highlights

Phosphodiesterases (PDEs) are a group of enzymes that catalyze the breakdown of cyclic adenosine monophosphate and cyclic guanosine monophosphate to their inactive form
Roflumilast analogs are a group of drugs which act as selective photodiesterase (PDE-4) inhibitor for the treatment severe chronic pulmonary disease associated with chronic brochnonities
PDE4 is the principal selective cyclic adenosine monophosphate metabolizing enzyme in inflammatory and immune cells which is highly expressed in leukocytes and other inflammatory cells involved in the pathogenesis of inflammatory lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD).[1]

Summary

Introduction

Phosphodiesterases (PDEs) are a group of enzymes that catalyze the breakdown of cyclic adenosine monophosphate and cyclic guanosine monophosphate to their inactive form. Structural identification of degradation products using high resolution mass spectrometry and theoretical investigation by density functional theory have been successfully carried out on roflumilast to identify four degradation products namely, 3,5-dichloropyridin-4-amine, N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-hydroxy benzamide, N-(3,5-dichloropyridin-4-yl)-3-(cyclopropylmethoxy)-4-(difluoromethoxy) benzamide and 3-(cyclopropylmethoxy)-N(3,5-dichloro-1-oxidopyridin-4-yl)-4-(difluoro methoxy) benzamide, generated in alkali, acidic and oxidative conditions.

Results

Conclusion