title: 2-Iminohomopiperidinium salts as selective inhibitors of inducible nitric oxide synthase (iNOS).
abstract: An attractive approach to the treatment of inflammatory conditions such as osteo- and rheumatoid arthritis, inflammatory bowel disease, and sepsis is through the selective inhibition of human inducible nitric oxide synthase (hiNOS) since localized excess nitric oxide (NO) release has been implicated in the pathology of these diseases. A series of monosubstituted iminohomopiperidinium salts possessing lipophilic functionality at ring positions 3, 5, 6, and 7 has been synthesized, and series members have demonstrated the ability to inhibit the hiNOS isoform with an IC50 as low as 160 nM (7). Compounds were found that selectively inhibit hiNOS over the human endothelial constitutive enzyme (heNOS) 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 constitutive enzyme (hnNOS) are comparable. Substitution in the 3 and 7 positions 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 also found to be orally bioavailable and efficacious due to their ability to inhibit the increase in plasma nitrite/nitrate levels in a rat LPS model.
authors.affiliation: Department of Discovery Medicinal Chemistry, G. D. Searle Research and Development, 4901 Searle Parkway, Skokie, Illinois 60077, USA.
authors.forename: D W
authors.initials: DW
authors.lastname: Hansen
authors.forename: K B
authors.initials: KB
authors.lastname: Peterson
authors.forename: M
authors.initials: M
authors.lastname: Trivedi
authors.forename: S W
authors.initials: SW
authors.lastname: Kramer
authors.forename: R K
authors.initials: RK
authors.lastname: Webber
authors.forename: F S
authors.initials: FS
authors.lastname: Tjoeng
authors.forename: W M
authors.initials: WM
authors.lastname: Moore
authors.forename: G M
authors.initials: GM
authors.lastname: Jerome
authors.forename: C M
authors.initials: CM
authors.lastname: Kornmeier
authors.forename: P T
authors.initials: PT
authors.lastname: Manning
authors.forename: J R
authors.initials: JR
authors.lastname: Connor
authors.forename: T P
authors.initials: TP
authors.lastname: Misko
authors.forename: M G
authors.initials: MG
authors.lastname: Currie
authors.forename: B S
authors.initials: BS
authors.lastname: Pitzele
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D001381:Azepines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D002460:Cell Line; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007097:Imines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D007249:Inflammation / Q000097:blood / Q000139:chemically induced; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D051381:Rats; D011917:Rats, Inbred Lew; D011994:Recombinant Proteins / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C111905:7-(2-ethylbutyl)hexahydro-1H-azepin-2-imine; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001381:Azepines; D004791:Enzyme Inhibitors; D007097:Imines; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; C111903:hexahydro-3-(2-propenyl)-1H-azepin-2-imine; C111904:hexahydro-7-propyl-1H-azepin-2-imine; C496320:NOS1 protein, human; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496321:Nos1 protein, mouse; C496322:Nos1 protein, rat; C496315:Nos3 protein, mouse; C496316:Nos3 protein, rat