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.

No abstract

Smith for preparative tic, to the Special Synthesis group under the direction of Drs. W. M. Hoehn and J. Witt for some starting materials, and to Mr. M. H. Stealey for his skillful technical assistance. Thanks are due to Dr. F. B. Colton for helpful discussion on this work and revision of the manuscript. Styryl glyoxal (5) for large-scale preparation of compound 6 and 7 has been supplied by Dr.

No abstract

trans-1 -(l-Fluoro-3-naphthyl )-2-(o-iodophenyl )ethylene (4b).-Using the above procedure with o-iodobenz aldehyde, colorless needles were obtained, mp 85.5-86.5°.