Effect of some hexahydroimidazo[1,2-c]pyrimidines in inflammatory responses involving leucocytes and macrophages

• Published in: Journal of pharmacy and pharmacology Vol. 53; no. 10; p. 1379
• Main Authors: Vidal, A, Ferrándiz, M L, Ubeda, A, Acero-Alarcon, A, Sepulveda-Arques, J, Alcaraz, M J
• Format: Journal Article
• Language: English
• Published: England 01.10.2001
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Carrageenan; Dinoprostone - metabolism; Edema - chemically induced; Edema - pathology; Female; Humans; Imidazoles - chemical synthesis; Imidazoles - pharmacology; In Vitro Techniques; Inflammation - chemically induced; Inflammation - pathology; Inflammation - prevention & control; Leukocytes - drug effects; Leukocytes - pathology; Leukotriene B4 - metabolism; Macrophages - drug effects; Macrophages - pathology; Macrophages, Peritoneal - drug effects; Macrophages, Peritoneal - metabolism; Mice; Neutrophils - drug effects; Neutrophils - enzymology; Nitrites - metabolism; Pancreatic Elastase - metabolism; Peroxidase - metabolism; Pyrimidines - chemical synthesis; Pyrimidines - pharmacology; Superoxides - metabolism; Zymosan
• ISSN: 0022-3573
• DOI: 10.1211/0022357011777729

We have studied the effects of some hexahydroimidazo[1,2-c]pyrimidine derivatives (HIPs) on leucocyte functions in-vitro and we have assayed the anti-inflammatory activity of these compounds in two models of inflammation. All HIPs inhibited the human neutrophil degranulation process and superoxide generation at concentrations in the microM range. In mouse peritoneal macrophages stimulated with lipopolysaccharide, HIP-4 and HIP-5 inhibited nitrite production without affecting prostaglandin E2 (PGE2) accumulation. HIP-4 was also active in the zymosan-injected mouse air pouch model (at 100 nmol/pouch), with significant reductions in leucocyte migration and PGE2 and leukotriene B4 levels in the air pouch exudate. To confirm the anti-inflammatory effects of this compound, we tested HIP-4 orally (10-40 mg kg(-1)) on carrageenan mouse-paw oedema where it exerted a dose-dependent inhibition of paw swelling with significant reductions of myeloperoxidase and elastase activity and PGE2 levels in paw homogenates. This study demonstrates that some HIPs inhibit leucocyte functions and one of these derivatives (HIP-4) shows anti-inflammatory activity when administered by the oral route, which can be related to inhibition of leucocyte migration.