2-Iminopyrrolidines as potent and selective inhibitors of human inducible nitric oxide synthase.

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Hagen TJ, Bergmanis AA, Kramer SW, Fok KF, Schmelzer AE, Pitzele BS, Swenton L, Jerome GM, Kornmeier CM, Moore WM, Branson LF, Connor JR, Manning PT, Currie MG, Hallinan EA

2-Iminopyrrolidines as potent and selective inhibitors of human inducible nitric oxide synthase.

J Med Chem. 1998 Sep 10;41(19):3675-83.

PubMed ID

9733492 [ View in PubMed

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Abstract

A series of substituted 2-iminopyrrolidines has been prepared and shown to be potent and selective inhibitors of the human inducible nitric oxide synthase (hiNOS) isoform versus the human endothelial nitric oxide synthase (heNOS) and the human neuronal nitric oxide synthase (hnNOS). Simple substitutions at the 3-, 4-, or 5-position afforded more potent analogues than the parent 2-iminopyrrolidine 1. The effect of ring substitutions on both potency and selectivity for the different NOS isoforms is described. Substitution at the 4- and 5-positions of the 2-iminopyrrolidine yielded both potent and selective inhibitors of hiNOS. In particular, (+)-cis-4-methyl-5-pentylpyrrolidin-2-imine, monohydrochloride (20), displayed potent inhibition of hiNOS (IC50 = 0.25 microM) and selectivities of 897 (heNOS IC50/hiNOS IC50) and 13 (hnNOS IC50/hiNOS IC50). Example 20 was shown to be an efficacious inhibitor of NO production in the mouse endotoxin assay. Furthermore, 20 displayed in vivo selectivity, versus heNOS isoform, by not elevating blood pressure at multiples of the effective dose in the mouse.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Nitroarginine	Nitric oxide synthase, brain	IC 50 (nM)	500	N/A	N/A	Details
Nitroarginine	Nitric oxide synthase, endothelial	IC 50 (nM)	500	N/A	N/A	Details