Synthesis and Biological Characterization of L-N⁶-(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.

Role of Nitric Oxide in Chronic Allergen-Induced Airway Cell Proliferation and Inflammation

“…We have used a prodrug, SC-51, which is converted rapidly in the blood to its active moiety, L-NIL, which in turn has selective inhibitory activity on NOS2 (Hallinan et al, 2002). SC-51 has been demonstrated to have anti-inflammatory properties.…”

“…SC-51 has been demonstrated to have anti-inflammatory properties. It reduced paw swelling in a rat model of carrageenan-induced acute paw inflammation with an ED 50 of 10 mg/kg (Hallinan et al, 2002). In our previous study, we examined the effect of a single dose of SC-51 (10 mg ⅐ kg Ϫ1 ) on the acute effects of single allergen exposure in sensitized Brown-Norway rats.…”

“…SC-51 itself has little activity as an inhibitor of NOS2 but is rapidly metabolized to L-NIL in the systemic circulation after oral administration in the rat. The IC 50 values for human NOS2 of L-NIL is 5.9 M, with lesser activities for NOS3 (IC 50 ϭ 138 M) and NOS1 (35 M); SC-51 itself has an IC 50 of Ͼ1850 M for these three NOS (Hallinan et al, 2002). In the rat, oral doses of up to 10 mg/kg inhibited the elevated plasma nitrite levels of rats treated with endotoxin with an ED 50 of 0.6 mg/kg (Hallinan et al, 2002).…”

Óxido nítrico: propriedades e potenciais usos terapêuticos

“…Um exemplo é a síntese de um derivado tetrazólico do NIL 37 , o qual se mostrou muito promissor em estudos pré-clínicos e clíni-cos de processos inflamatórios, atuando como uma pró-droga (composto inativo que, ao ser metabolizado, é convertido na droga ativa) do NIL e inibindo seletivamente a iNOS.…”

Disposition and Pharmacokinetics of L-N6-(1-Iminoethyl)Lysine-5-Tetrazole-Amide, a Selective iNOS Inhibitor, in Rats

“…7,8,[13][14][15][16] L-N6-(1-iminoethyl)lysine-5-tetrazole-amide (L-NIL-TA), is a selective iNOS inhibitor. 17 It has been under development as a therapeutic agent for the treatment of OA. L-NIL-TA is an orally administered inactive prodrug that undergoes rapid amide hydrolysis in vivo to the pharmacologically active iNOS inhibitor, L-N6-(1-iminoethyl)lysine (L-NIL).…”