In continual efforts to find potentially safer and more efficacious parent agents through
further exploration of SAR of this class, we decided to study the pharmacological profiles of compounds 5a, b, f, g belonging to pyrazolopyrimidopyrimidine family. We examined the effect of modification of the electronic nature of substituents on various portions of type NSAIDs. For this objective the hydrogen atom (position 5) is replaced by methyl or ethyl group, even and for more important anti-inflammatory activity, the cyano function is replaced by ester function. Table 2 reveals the results of the intraperitoneal administration of the compounds
5a, b, f, g in this website carrageenan-induced rat paw oedema. The compounds 5a, b, f, g tested at 50 and 100 mg/kg, i.p. KU55933 cost produced a significant reduction of the oedema throughout the entire period of observation in a dose-dependent manner. The highest reduction of the oedema was at 3 h after carrageen injection with a percent inhibition ranged, from 40.64 to 56.81 % for compound 5a, from 58.98 to 71.36 % for compound 5b, from 60.02 to 82.83 % for compound 5f and from 28.75 to 42.87 % for compound 5g, whereas the reference drug (acetylsalicylic–lysine, 300 mg/kg, i.p.) produced 48.03 % reduction in paw volume. The influence of the substituent R2 on activity is remarkable. Compound 5a is less potent than the 5-methyl derivatives 5b, so a methyl group linked to the pyrimidine cycle
increases the activity compared to the case of a hydrogen atom. At the same dose (100 mg/kg), compound 5b produced 71.36 % inhibition of oedema against 56.81 % for 5a. In Ilomastat in vivo addition, the compound 5f is more potent than the ethyl derivatives 5g, so an ethyl group linked to the pyrimidine cycle decreases the activity compared to the methyl group. Table 2 Anti-inflammatory effect of the intraperitoneal administration of 5a, b, f, g and of the reference drug (acetylsalicylic–lysine: ASL) in carrageenan-induced rat paw oedema Sample Dose (mg/kg) Oedema (10−2 ml) Calpain (mean ± SEM) Oedema inhibition (%) 1 h 3 h 5 h 1 h 3 h 5 h Vehicle (2,5 ml/kg) – 35.87 ± 4.48 50.66 ± 3.68 56.04 ± 2.91 – – – Acetylsalicylic–lysine (reference drug) 300 13.23 ± 2.69** 26.32 ± 2.44** 29.15 ± 2.87** 63.10 48.03 47.98 5a 50 20.59 ± 2.51* 30.07 ± 3.51* 33.73 ± 4.16* 42.59 40.64 39.8 100 7.01 ± 3.41** 21.88 ± 1.89** 23.45 ± 2.5** 80.44 56.81 58.15 5b 50 14.62 ± 3.21* 20.78 ± 2* 23.56 ± 2* 59.25 58.98 57.95 100 2.81 ± 2.06*** 14.51 ± 2.98*** 20.86 ± 2.21*** 92.17 71.36 62.76 5f 50 13.51 ± 3.4** 20.25 ± 2.8** 22.74 ± 3.2** 62.31 60.02 59.42 100 2.07 ± 2.8*** 8.69 ± 2.3*** 17.45 ± 2.5*** 94.22 82.83 68.85 5g 50 24.37 ± 2.7* 36.09 ± 2.9* 41.95 ± 2.8 32.04 28.75 25.