Exploration of the 5-bromopyrimidin-4(3H)-ones as potent inhibitors of PDE5

Thermodynamic and Structural Characterization of Halogen Bonding in Protein–Ligand Interactions: A Case Study of PDE5 and Its Inhibitors

“…Expression, purification, and crystallization of the catalytic domain of recombinant human PDE5A1, and the synthesis of the five compounds are the same as that described in our previous studies. ,, The purity of all five compounds was >95% as confirmed by HPLC. Inhibitors 1 and 5 were dissolved in the precipitant solution to reach a final concentration of 0.5 mM for soaking.…”

“…29,30 We have previously described the design, synthesis, and pharmacological evaluation of monocyclic pyrimidinones as novel inhibitors of PDE5. 11,31,32 To introduce halogen bonding between halogen atom of inhibitors and the hydroxyl oxygen atom of residue Y612 at the active-site of PDE5, the 5-position of the pyrimidinone ring was substituted by halogens (Figure 1A). 11 On the basis of our previous work, we here present a comprehensive thermodynamic study on the binding of PDE5 with five inhibitors which share an identical structure scaffold but have different substituents, H, F, Cl, Br, and I, at the 5position of the pyrimidinone ring (Figure 1A).…”

Pharmacokinetics-Driven Optimization of 4(3H)-Pyrimidinones as Phosphodiesterase Type 5 Inhibitors Leading to TPN171, a Clinical Candidate for the Treatment of Pulmonary Arterial Hypertension

“…We previously described the discovery of a series of 4­(3 H )-pyrimidinones as novel, potent, and selective inhibitors of PDE5 for potential use in PAH as well as male erectile dysfunction (ED). − The 11 subfamilies of human PDEs (PDE1–11) possess a conserved C-terminal catalytic domain for hydrolysis of the ubiquitous second messenger, cyclic adenosine monophosphate (cAMP) and cGMP . High selectivity is thus crucial to a PDE5 inhibitor as each PDE isozyme acts as a key element in regulation of some physiological processes, and inhibition of other PDE isozymes rather than PDE5 may lead to off-target-based adverse effects .…”

Design and synthesis of novel 5-(3,4,5-trimethoxybenzoyl)-4-aminopyrimidine derivatives as potent and selective phosphodiesterase 5 inhibitors: Scaffold hopping using a pseudo-ring by intramolecular hydrogen bond formation

“…1 Therefore, orally available PDE5 inhibitors are used for the treatment of male erectile dysfunction as first-line therapy. 2,3 In the USA, sildenafil (1), vardenafil, and tadalafil were approved by the FDA in 1998FDA in , 2003FDA in , and 2003 In addition to these marketed drugs, PDE5 inhibitors having various frameworks, such as phthaladine, 7 quinazoline, 8 quinolone, 9 pyrazolopyrimidine, 10 pyridopyrazinone, 11 and pyrimidine-4(3H)-one 12 have been reported to date.…”