Design Synthesis and Pharmacological Evaluation of Novel Phosphodiesterase FourInhibitors for their Anti Depressant and Anxiolytic Potential
AUTHOR | Sudali, Muthu Venkatesh |
PUBLISHER | Rj Publishers (01/08/2023) |
PRODUCT TYPE | Paperback (Paperback) |
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.
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.