Structure-Based Design and Synthesis of N-Nitro-L-Arginine-Containing Peptidomimetics as Se
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- 作者：Jiwon Seo ; Jotato Igarashi ; Huiying Li ; Pavel Martá ; sek ; Linda J. Roman ; Thomas L. Poulos ; Richard B. Silverman
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：May 3, 2007
- 年：2007
- 卷：50
- 期：9
- 页码：2089 - 2099
- 全文大小：706K
- 年卷期：v.50,no.9(May 3, 2007)
- ISSN：1520-4804
文摘
The neuronal isoform of nitric oxide synthase (nNOS), the enzyme responsible for the production of nitricoxide in the central nervous system, represents an attractive target for the treatment of variousneurodegenerative disorders. X-ray crystal structures of complexes of nNOS with two nNOS-selectiveinhibitors, (4S)-N-{4-amino-5-[(2-aminoethylamino]pentyl}-N'-nitroguanidine (1) and 4-N-(N
ges/gifchars/omega.gif" BORDER=0 >-nitro-L-argininyl)-trans-4-amino-L-proline amide (2), led to the discovery of a conserved structural water moleculethat was hydrogen bonded between the two heme propionates and the inhibitors (Figure 2). On the basis ofthis observation, we hypothesized that by attaching a hydrogen bond donor group to the amide nitrogen of2 or to the secondary amine nitrogen of 1, the inhibitor molecules could displace the structural water moleculeand obtain a direct interaction with the heme cofactor. To test this hypothesis, peptidomimetic analogues3-5, which have either an N-hydroxyl (3 and 5) or N-amino (4) donor group, were designed and synthesized.X-ray crystal structures of nNOS with inhibitors 3 and 5 bound verified that the N-hydroxyl group had,indeed, displaced the structural water molecule and provided a direct interaction with the heme propionatemoiety (Figures 5 and 6). Surprisingly, in vitro activity assay results indicated that the addition of a hydroxylgroup (3) only increased the potency slightly against the neuronal isoform over the parent compound (1).Rationalizations for the small increase in potency are consistent with other changes in the crystal structures.