2-IMINOHOMOPIPERIDINIUM SALTS AS SELECTIVE INHIBITORS OF INDUCIBLE NITRIC-OXIDE SYNTHASE (INOS)

An attractive approach to the treatment of inflammatory conditions suc h as osteo-and rheumatoid arthritis, inflammatory bowel disease, and s epsis is through the selective inhibition of human inducible nitric ox ide synthase (hiNOS) since localized excess nitric oxide (NO) release has been implicated in the pathology of these diseases. A series of mo nosubstituted iminohomopiperidinium salts possessing lipophilic functi onality at ring positions 3, 5, 6, and 7 has been synthesized, and ser ies members have demonstrated the ability to inhibit the hiNOS isoform with an IC50 as low as 160 nM (7). Compounds were found that selectiv ely inhibit hiNOS over the human endothelial constitutive enzyme (heNO S) with a heNOS/hiNOS IC50 ratio in excess of 100 and as high as 314 ( 9). Potencies for inhibition of hiNOS and the human neuronal constitut ive enzyme (hnNOS) are comparable. Substitution in the 3 and 7 positio ns provides compounds that exhibit the greatest degree of selectivity for hiNOS and hnNOS over heNOS. Submicromolar potencies for 6 and 7 in a mouse RAW cell assay demonstrated the ability of these compounds to inhibit iNOS in a cellular environment. These latter compounds were a lso found to be orally bioavailable and efficacious due to their abili ty to inhibit the increase in plasma nitrite/nitrate levels in a rat L PS model.