Synthesis and biological characterization of L-N(6)-(1-iminoethyl)lysine 5-tetrazole-amide, a prodrug of a selective iNOS inhibitor.
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.
Hallinan
E Ann
EA
Department of Arthritis and Inflammation Pharmacology, Pharmacia Corporation, 4901 Searle Parkway, Skokie, Illinois 60077, USA. ann.hallinan@pharmacia.com
Tsymbalov
Sofya
S
Dorn
Clifford R
CR
Pitzele
Barnett S
BS
Hansen
Donald W
DW
Moore
William M
WM
Jerome
Gina M
GM
Connor
Jane R
JR
Branson
Linda F
LF
Widomski
Deborah L
DL
Zhang
Yan
Y
Currie
Mark G
MG
Manning
Pamela T
PT
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
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