PMID: 11931623Apr 5, 2002Paper

Synthesis and biological characterization of L-N(6)-(1-iminoethyl)lysine 5-tetrazole-amide, a prodrug of a selective iNOS inhibitor

Journal of Medicinal Chemistry
E Ann HallinanPamela T Manning

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.

References

Jan 1, 1990·Proceedings of the National Academy of Sciences of the United States of America·D S Bredt, S H Snyder
Nov 11, 1994·Journal of Medicinal Chemistry·W M MooreM G Currie
Jan 24, 1995·European Journal of Pharmacology·J R ConnorM G Currie
Aug 1, 1993·Proceedings of the National Academy of Sciences of the United States of America·D SalveminiP Needleman
Jun 1, 1996·British Journal of Pharmacology·D SalveminiM G Currie
May 15, 1996·European Journal of Pharmacology·D SalveminiP T Manning
Dec 24, 1996·Proceedings of the National Academy of Sciences of the United States of America·L M LandinoL J Marnett
Jan 20, 1998·Trends in Biochemical Sciences·B Mayer, B Hemmens
May 20, 1999·Annual Review of Pharmacology and Toxicology·A J HobbsS Moncada

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Citations

Sep 27, 2002·European Journal of Pharmacology·Paul R EynottK Fan Chung
Dec 4, 2002·Nature Reviews. Drug Discovery·Patrick Vallance, James Leiper
Apr 7, 2009·European Journal of Pharmacology·Prabhakara Reddy NagareddyKathleen M MacLeod
Oct 13, 2004·Mutation Research·Chinthalapally V Rao
Nov 30, 2002·Experimental Eye Research·Arthur H NeufeldPamela T Manning
Sep 19, 2012·Mediators of Inflammation·Jan VítečekLukáš Kubala
Dec 21, 2004·World Journal of Gastroenterology : WJG·Yong-Zhong WangXiao-Ying Cha
Sep 17, 2004·American Journal of Physiology. Regulatory, Integrative and Comparative Physiology·Yunpeng DuT S Kern
Jun 14, 2019·Medicinal Research Reviews·Maris A CinelliRichard B Silverman
Dec 20, 2002·The Journal of Pharmacology and Experimental Therapeutics·Paul R EynottK Fan Chung
May 10, 2003·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Trevor T HanselPeter J Barnes
Sep 11, 2019·Medicinal Research Reviews·Richa MinhasGulshan Bansal
Sep 9, 2019·Archives of Biochemistry and Biophysics·Stefanie BrandsErwin A Galinski
Apr 5, 2019·The Journal of Organic Chemistry·Phongprapan NimnualKunlayanee Punjajom

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