monash_89017.pdf (4.86 MB)
Small molecule inhibitors of PDE4
thesisposted on 2017-02-06, 05:16 authored by Nankervis, Jacob Leonard
The phosphodiesterase 4 (PDE4) family of enzymes is a promising drug target for a variety of conditions, including inflammatory conditions such as asthma and chronic obstructive pulmonary disorder (COPD), and neurological conditions such as depression. PDE4 inhibitors include rolipram, which was trialled for the treatment of depression, and roflumilast, which has recently completed clinical trials for the treatment of COPD. Unfortunately, PDE4 inhibitors generally exhibit side effects – mainly, nausea and emesis. The mechanisms underlying these side effects are not fully understood, though several strategies exist in the literature for avoiding them. These strategies usually encourage finding novel structural classes of inhibitors. Here I present work on two structural classes as PDE4 inhibitors. Chapter one introduces the PDE4 enzyme as a drug target and explains the side effects associated with it, and introduces previously studied inhibitor classes. Chapter two describes the synthesis and evaluation of a class of tetrahydrobenzothiophenes as PDE4 inhibitors, with the most potent analogue exhibiting an IC50 of approximately 20 nM. Although this class was serendipitously discovered by my lab and collaborators, a similar compound was recently reported by Kranz et. al. as a selective PDE4B inhibitor. Interestingly, our compounds bind in the active site of PDE4 in a different orientation, as revealed by X-ray co-crystallography. Chapter three builds on this structural information, using molecular docking to design new analogues. Based on docking simulations, the tetrahydrobenzothiophene scaffold was derivatised with different urea groups, with the most potent exhibiting a PDE4 IC50 of 93.03 nM. Additionally, isomeric analogues of the tetrahydrobenzothiophenes of chapter 2 were investigated, though these performed poorly in assays. Chapter four describes flavonoids as a possible source of PDE4 inhibitors. Flavonoids are a class of naturally occurring polyphenolic compounds that display a range of biological activities. There have been some indications that this class may be a useful source of phosphodiesterase inhibitors. Here I investigated a series of chromone compounds bearing a 2-tetrahydopyranyl group. In PDE4 assays, the most potent compounds exhibited IC50s of approximately 0.4 μM.