Relaxant effects of selected sildenafil analogues in the rat aorta

Figures & data

Figure 1. Structure of sildenafil and its new analogues. The data are the means of four experiments ± S.E.M.

Scheme 1. Synthetic pathway to the sildenafil analogues (8a–m). Reagents and conditions: (a) CH₃CH₂CH₂CH₂NO₂ (for R = C₃H₇) or CH₃CH₂NO₂ (for R = CH₃), KOH, DMSO, 2 h, 80–86%; (b) Na₂S₂O₄, H₂O/dioxane, rt, 12 h, 55–65%; (c) CH₃NH–NH₂, PTSA, EtOH, rt, 1 h, 50–55%; (d) method A: 10% HCl, EtOH, reflux, 1 h, 58–61%; method B: PTSA, 140 °C, 1 min, 61%; (e) ethoxyphenylboronic acid, Pd(PPh₃)₄, CuMeSal, THF, Ar, reflux, overnight, 75–80%; (f); ClSO₃H, 0 °C to rt, 2 h, 75–95%; (g) appropriate amine, anhydrous MeCN, rt, overnight, 72–93%.

Figure 2. Effects of tested compounds on vascular tension in the endothelium-intact, KCl (60 mM) precontracted aortic rings. The data are the means of four experiments ± S.E.M.

Table 1. Vasorelaxant potencies of tested compounds on sustained contraction of aortic rings induced by KCl depolarising solution (60 mM).

			E (+)		E (−)
Compound	R	R^1	IC50 (µM)	Maximal relaxation (at 300 µM) (%)	IC50 (µM)	Maximal relaxation (at 300 µM) (%)	n
8a	C3H7		48.9 ± 3.l	100	39.7 ± 5.6	100	4
8b	CH3		178.1 ± 25.2	94.7	143.8 ± 55.0	89.4	4
8c	CH3		128.1 ± 11.3	94.8	100.0 ± 5.2	90	4
8d	CH3		–	52.4	–	37.4	4
8e	CH3		–	65.6	–	48.2	4
8f	CH3		120.0 ± 4.7	96.7	108.3 ± 9.5	92	4
8g	CH3		118.0 ± 3.9	98.9	100.2 ± 4.8	93	4
Sildenafil			7.0 ± 1.0	90.0	14.3 ± 3.2	85	4
IBMX			39.3 ± 3.8	96.2	26.4 ± 9.3	88.4	4

Aortic rings with functional endothelium (E +) and without endothelium (E −). The data are the means of four experiments ± S.E.M.

Figure 3. Vasorelaxant effects of compound (8a) on KCl and phenylephrine-induced contractions in isolated endothelium-intact E(+) and denuded E(−) rat aorta. (♦) KCl E(+), (▪) KCl E(−), (▴) phenylephrine E(+), (□) phenylephrine E(−). The data are the means of 4–8 experiments ± S.E.M.

Figure 4. Additive effects of compound (8a) and IBMX (1 µM) on rat aortic rings precontracted by phenylephrine (10 µM). The data are the means of four experiments ± S.E.M.

Figure 5. The vasorelaxant effect of compound (8a) on endothelium intact rat aorta precontracted by phenylephrine (10 μM) in the absence and presence of l-NAME (10 μM), ODQ (1 μM), glibenclamide (1 μM). The data are the means of four experiments ± S.E.M.

Figure 6. Effect of compound (8a) (30 µM) on isoprenaline-induced vasorelaxation in endothelium denuded rat aorta precontracted by phenylephrine (10 µM).

Figure 7. The effect of compound (8a) and sildenafil on blood pressure in anesthetized rats at a dose of 10 mg/kg i.p. The data are the means of 5–6 experiments ± S.E.M. Statistical analyses were performed using a one-way ANOVA test, post hoc Dunnet test; *p < 0.05; **p < 0.02.