title: Synthesis and biological characterization of L-N(6)-(1-iminoethyl)lysine 5-tetrazole-amide, a prodrug of a selective iNOS inhibitor.
abstract: The 5-tetrazole amide of L-N(6)-(1-iminoethyl)lysine (L-NIL), L-N(6)-(1-iminoethyl)lysine 5-tetrazole amide (1), has been prepared and evaluated. In contrast to L-NIL, 1 is a stable, nonhygroscopic, crystalline solid. Unlike L-NIL, 1 has minimal inhibitory activity in vitro on human inducible nitric oxide synthase (iNOS). However, it is rapidly converted in vivo to L-NIL and produces dose-dependent inhibition of iNOS in acute and chronic models of inflammation in the rodent with efficacy comparable to L-NIL. In addition, both 1 and L-NIL exhibit significant and comparable in vivo selectivity for the inhibition of iNOS vs endothelial NOS. Doses approximately 80-fold greater than those that inhibited inflammation do not elevate systemic blood pressure. In summary, both the physical properties and the pharmacological profile of 1 make it an ideal molecule for preclinical and clinical studies on the role of selective iNOS inhibitors in mediating inflammatory disease processes.
authors.affiliation: Department of Arthritis and Inflammation Pharmacology, Pharmacia Corporation, 4901 Searle Parkway, Skokie, Illinois 60077, USA. ann.hallinan@pharmacia.com
authors.forename: E Ann
authors.initials: EA
authors.lastname: Hallinan
authors.forename: Sofya
authors.initials: S
authors.lastname: Tsymbalov
authors.forename: Clifford R
authors.initials: CR
authors.lastname: Dorn
authors.forename: Barnett S
authors.initials: BS
authors.lastname: Pitzele
authors.forename: Donald W
authors.initials: DW
authors.lastname: Hansen
authors.forename: William M
authors.initials: WM
authors.lastname: Moore
authors.forename: Gina M
authors.initials: GM
authors.lastname: Jerome
authors.forename: Jane R
authors.initials: JR
authors.lastname: Connor
authors.forename: Linda F
authors.initials: LF
authors.lastname: Branson
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Widomski
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Mark G
authors.initials: MG
authors.lastname: Currie
authors.forename: Pamela T
authors.initials: PT
authors.lastname: Manning
mesh_terms: D000208:Acute Disease; D000284:Administration, Oral; D000818:Animals; D001169:Arthritis, Experimental / Q000473:pathology; D002351:Carrageenan; D002908:Chronic Disease; D003460:Crystallization; D004487:Edema / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D006709:Homoarginine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008239:Lysine / Q000031:analogs & derivatives* / Q000737:chemistry*; 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; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors
chemical_list: D004791:Enzyme Inhibitors; D007527:Isoenzymes; C446200:L-N(6)-(1-iminoethyl)lysine tetrazole-amide; C090663:N(6)-(1-iminoethyl)lysine; D011355:Prodrugs; D011994:Recombinant Proteins; D006709:Homoarginine; D002351:Carrageenan; C496320:NOS1 protein, human; C496319:NOS2 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; C496322:Nos1 protein, rat; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; D008239:Lysine