Discovery of Potent Cyclic GMP Phosphodiesterase Inhibitors. 2-Pyridyl- and 2-Imidazolylquinazolines Possessing Cyclic GMP Phosphodiesterase and Thromboxane Synthesis Inhibitory Activities

Abstract

Moderate cyclic GMP phosphodiesterase (cGMP-PDE, PDE V) inhibitor 2-phenyl-4-anilino-quinazoline (1) was identified utilizing MultiCASE assisted drug design (MCADD) technology. Modification of compound 1 was conducted at the 2-, 4-, and 6-positions of the quinazoline ring for enhancement of cGMP-PDE inhibitory activity. The 6-substituted 2-(imidazol-1-yl)-quinazolines are 1000 times more potent in in vitro PDE V enzyme than the well-known inhibitor zaprinast. The 6-substituted derivatives of 2-(3-pyridyl)quinazoline 84 and 2-(imidazol-1-yl)quinazoline 86 exhibited more than 1000-fold selectivity for PDE V over the other four PDE isozymes. In addition, cGMP-PDE inhibitors 64, 65, and 73 were found to have an additional property of thromboxane synthesis inhibitory activity.

cAMP-dependent phosphodiesterase inhibition and SAR studies on novel 6,8-disubstituted 2-phenyl-3-(substituted benzothiazole-2-yl)-4[3H]-quinazolinone

“…Quinazolines (Fig. 2), bio-isosteres of xanthines, possess PDEs inhibitory activity (Rotella et al, 2000a, b;Macor et al, 1999;Lee, 1994;Lee et al,1994). Based on these observations, a hypothetical model (Fig.…”

Synthesis of 4‐Aminoquinazolines by Palladium‐Catalyzed Intramolecular Imidoylation of N‐(2‐Bromoaryl)amidines

“…Several of the products shown in Scheme display pharmaceutically important biological activities. For example, compound 1 ad inhibits phosphodiesterase V (PDE 5) with an IC 50 of 320 n M 18. Furthermore, compound 1 ab was recently reported to display topoisomerase I inhibitory activity equal to camptothecin 11.…”

“…For example, compound 1 ad inhibits phosphodiesterase V (PDE 5) with an IC 50 of 320 nm. [18] Furthermore, compound 1 ab was recently reported to display topoisomerase I inhibitory activity Scheme 3. Study of the scope of our Pd-catalyzed isocyanide insertion reaction: synthesis of 4-aminoquinazolines 1 aa-1 la.…”

Substituent Groups

“…However, this acetylenic analog is reactive and rapidly metabolized, giving, for example, Michael addition in a biological system, and thus led the authors not to test this compound further [56]. This additional interaction with the receptor increased the potency of this compound five times when compared to the 6-chloro analog.…”