Synthesis and Structure-Activity Relationship of N-Arylrolipram Derivatives as Inhibitors of PDE4 Isozymes.

The Next Generation of Phosphodiesterase Inhibitors: Structural Clues to Ligand and Substrate Selectivity of Phosphodiesterases

“…The X-ray data will certainly assist in our attempts to understand the basis for the enhancements in potency shown by PDE4 inhibitors such as cilomilast ( 16 ) and roflumilast ( 17 ), which are in very advanced clinical evaluation for asthma and chronic obstructive pulmonary disease and are clearly related to rolipram with respect to the catechol ether moiety . In addition, extended structures such as N -aryl analogues (e.g., 18 ) have been reported that exhibit enhanced potency and stereoselectivity relative to rolipram . Whether these extended substituents target specific binding regions at the outer edge of the binding pocket and are analogous to those occupied by PDE5 inhibitors requires experimental clarification.…”

“…46 In addition, extended structures such as N-aryl analogues (e.g., 18) have been reported that exhibit enhanced potency and stereoselectivity relative to rolipram. 47 Whether these extended substituents target specific binding regions at the outer edge of the binding pocket and are analogous to those occupied by PDE5 inhibitors requires experimental clarification. While earlier docking studies failed to predict the crystallographic binding mode of rolipram, 29 there is now a sound basis for the theoretical analysis of current and future catechol ether-based inhibitor binding.…”

Phosphodiesterase-4 as a potential drug target

“…Cilomilast (3) and roflumilast (4), as described in Section 2.1 of this review, are currently in development for COPD. Several groups have designed compounds that are extended versions of the catechol series, such as the rolipram derivative described by Keller (21) [58], Celltech's CT-5357 (22) and pumafentrine (23), a dual PDE4/PDE3 inhibitor from Altana. Filaminast was developed by Wyeth for the treatment of asthma and it has been discontinued after Phase II trials [204].…”

Elucidation of a Structural Basis for the Inhibitor-Driven, p62 (SQSTM1)-Dependent Intracellular Redistribution of cAMP Phosphodiesterase-4A4 (PDE4A4)

“…(Bulky structural extensions from the rolipram lactam nitrogen, presumably directed to subsites around the rim of the catalytic pocket, are already known to support or enhance PDE4-inhibitory activity. ) Accordingly, we prepared both antipodes of N -methyl and N -benzyl rolipram for assessment (Scheme ). Significantly, the foci-inducing capacity of ( R )-rolipram was retained in both its N -methyl and N -benzyl derivatives (respectively, 10R and 11R ), supporting the notion that the inhibitor binding with its lactam ring in a solvent-orientated conformation drives foci formation.…”