ChemInform Abstract: Discovery of Potent Cyclic GMP Phosphodiesterase Inhibitors. 2‐Pyridyl‐ and 2‐Imidazolylquinazolines Possessing Cyclic GMP Phoshodiesterase and Thromboxane Synthesis Inhibitory Activities.

Abstract

Discovery of Potent Cyclic GMP Phosphodiesterase Inhibitors. 2-Pyridyl-and 2-Imidazolylquinazolines Possessing Cyclic GMP Phoshodiesterase and Thromboxane Synthesis Inhibitory Activities. -The structure of 2-phenyl-4-anilinoquinazoline, identified as moderate cyclic GMP phosphodiesterase (cGMP-PDE, PDE V) inhibitor, is modified ( ca. 70 examples) at the 2-, 4-, and 6-positions of the quinazoline ring, as demonstrated by derivatives of types (VII), (XI), (XIV), and ( XV). The 6-substituted quinazolines, e.g. (XVb) and (XVc), are 1000 times more potent with respect to their cGMP-PDE V inhibitory activity than the known inhibitor zaprinast. The cGMP-PDE inhibitors (VII), (XI) , and (XVa) also show thromboxane synthesis inhibitory activity. -(LEE, S. J.; KONISHI, Y.; YU, D. T.; MISKOWSKI, T. A.; RIVIELLO, C. M.; MACINA, O. T.; FRIERSON, M. R.; KONDO, K.; SUGITANI, M.; SIRCAR, J. C.; BLAZEJEWSKI, K. M.; J.

Targeting cyclic nucleotide phosphodiesterase 5 (PDE5) in brain: Toward the development of a PET radioligand labeled with fluorine-18

“…The quinoline scaffold bearing a hydroxymethyl group at position C-3 ("east region") improves the inhibitory activity on PDE5 and the solubility compared to the other core ring systems tested. The binding to the protein is highly dependent on the presence of the secondary amino functionality at position C-4 ("north region") [27]. Moreover, the influence of a combination of different substituents on positions C-6 and C-8 of the quinoline scaffold was studied resulting in the so far most potential candidates 1 [25] and 2 [26].…”

“…For introduction of the fluorine atom at the "north region" of the lead structures 1 and 2, modification of the chlorobenzene scaffold was intended ( Figure 1). As the secondary amine substituted at the C-4 position of the quinoline core is known to be crucial for the PDE5 inhibitory activity [27], it was not considered for an alkylation with a fluorinated alkyl side chain. In order to enable a straightforward radiofluorination, the substitution of a 2-fluoro-3methoxypyridine ring was favored (3 and 4).…”