Chemical, Biochemical, and Structural Similarities and Differences of Dermatological cAMP Phosphodiesterase-IV Inhibitors

Roflumilast, the third phosphodiesterase-IV (PDE4) inhibitor approved for use in dermatology, is indicated for topical treatment of psoriasis, seborrheic dermatitis, and atopic dermatitis, whereas its 2 predecessors, apremilast and crisaborole, are indicated for oral treatment of psoriasis and topical treatment of atopic dermatitis, respectively. All 3 are rationally designed PDE4 inhibitors, but roflumilast is the most potent and effective among the 3, with in vitro inhibitory constant half-maximal inhibitory concentration value of 0.7 nM (roflumilast), 0.14 μM (apremilast), and 0.24 μM (crisaborole), representing differences of over 3 orders of magnitude. PDE4 is a cAMP (an intracellular secondary messenger) hydrolase consisting of at least 4 subtypes of exon-spliced isoforms, which are primarily expressed in immune cells for inflammatory response. PDE4 inhibition lengthens the duration of cAMP signals and increases cellular cAMP concentrations, generating anti-inflammatory effects. We examined the physicochemical principles that make PDE4 inhibitors effective and propose chemical modifications to improve them. Sequence alignment of the catalytic domains of all phosphodiesterases identified many previously unreported invariant residues. These residues bind 1 Zn and 1 Mg ion plus 5 structural water molecules for orienting an attacking μ-hydroxyl/μ-oxo anion and for stabilizing 2 nonbridging phosphate oxygen atoms. The arrangement of the 2 divalent metal ions in phosphodiesterases is not related to that of the classic mechanism for general phosphoryl transfer.