Description

Phosphodiesterase-4(PDE4), an important component of the cyclic adenosine

monophosphate (cAMP) cascade, selectively metabolizes cAMP in the brain to the

inactive monophosphate. Their inhibitors may offer novel strategies in the treatment of

depression. However, its development as antidepressant drugs has been encumbered

by their side effects profile of non-selective PDE inhibitors like nausea, emesis,

gastrointestinal side-effects, and vascular toxicity. These side-effects can be minimized

by specifically targeting isozymes in the particular tissue or the cell of interest. So, we

were interested in developing novel, PDE4 inhibitors with better isozyme selectivity and

further explore their potential as anti-depressant and anxiolytics.

The novel pharmacophoric requirements derived from nitraquazone and its related

compounds as potential PDE4 inhibitors that include key elements: a) a planar scaffold

providing a HBA and b) two hydrophobic substituent's with their corresponding linker

(1 and 2). On the basis of the proposed pharmacophore, six different series of N4

substituted quinoxaline based carboxamides with variations on linker-1 and/or

unsubstituted/substituted hydrophobe, and while two series of N3 substituted quinazoline

based carboxamides which are positional isomer of quinoxaline-carboxamides were

designed as per the pharmacophoric requirements as novel PDE4 inhibitors.