4664419_monash_119310.pdf (23.6 MB)
Imidazoquinazolinone based inhibitors of Phosphodiesterase 3
thesisposted on 2017-02-17, 03:20 authored by Blackmore, Timothy Robert
Phosphodiesterases (PDE) catalyze the deactivation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Inhibiting a cell’s PDE increases the level of cAMP or cGMP in the cytosol, enhancing the cells response to stimuli. Selectively inhibiting a PDE subtype can cause a specific cell or tissue type to elicit a therapeutic response. In the past PDE3 inhibitors were designed as cardiac inotropic agents to replace cardiac glycosides and sympathomimetic drugs. Though they were effective, limitations due to serious side effects arose and PDE3 inhibitors were largely abandoned. Further research has found two isoforms of PDE3; PDE3A which is responsible for PDE3 inhibitors inotropic and antithrombotic effects, and PDE3B which is involved in the insulin signaling pathway. The majority of literature PDE3 inhibitors have not been examined for isoform selectivity between PDE3A and PDE3B. Inhibitors that select for either subtype will assist in delineating the physiological roles of these isoforms and may show improved therapeutic profiles. A variety of known and novel PDE3 inhibitors based on an imidazoquinazolinone scaffold were synthesized and screened against each isoform. A literature PDE3 inhibitor was found to be 13 fold selective for PDE3A over PDE3B and is the most selective PDE3A inhibitor identified to date. An improved synthetic route to analogous compounds was established. This approach was used to design and synthesize a focused library of compounds. From this library several potent novel PDE3 inhibitors were identified. Inspired by the structures known PDE inhibitors a series of novel compounds incorporating an imidazolidin-4-one ring were synthesized. The synthesis and derivatization of this structural motif was explored in an effort to use Fragment Based Drug Design to develop novel ligands for PDE inhibition or other therapeutic targets.