Chemical, biochemical, and structural similarities and differences of dermatological cAMP phosphodiesterase-IV inhibitors.

Abstract

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 two predecessors, apremilast and crisaborole, are indicated for oral treatment of psoriasis and topical treatment of atopic dermatitis, respectively. All three are rationally designed PDE4 inhibitors, but roflumilast is the most potent and effective among the three with in vitro inhibitory constant IC₅₀ value of: 0.7 nM (roflumilast), 0.14 μM (apremilast), and 0.24 μM (crisaborole), with differences of over 3 orders of magnitude. PDE4 is a 3',5'-cyclic adenosine monophosphate (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 PDEs identified many previously unreported invariant residues. These residues bind one Zn and one Mg ions plus five structural water molecules for orienting an attacking μ-hydroxyl/μ-oxo anion and for stabilizing two non-bridging phosphate oxygen atoms. The arrangement of the two divalent metal ions in PDEs is not related to that of the classic mechanism for general phosphoryl transfer.