4k5e Citations

Chiral linkers to improve selectivity of double-headed neuronal nitric oxide synthase inhibitors.

Bioorg. Med. Chem. Lett. (2013)
Related entries: 4k5d, 4k5f, 4k5g, 4k5h, 4k5i, 4k5j, 4k5k

Cited: 4 times
EuropePMC logo PMID: 23993333

Abstract

To develop potent and selective nNOS inhibitors, new double-headed molecules with chiral linkers that derive from natural amino acids or their derivatives have been designed. The new structures contain two ether bonds, which greatly simplifies the synthesis and accelerates structure optimization. Inhibitor (R)-6b exhibits a potency of 32nM against nNOS and is 475 and 244 more selective for nNOS over eNOS and iNOS, respectively. Crystal structures show that the additional binding between the aminomethyl moiety of 6b and the two heme propionates in nNOS, but not eNOS, is the structural basis for its high selectivity. This work demonstrates the importance of stereochemistry in this class of molecules, which significantly influences the potency and selectivity of the inhibitors. The structure-activity information gathered here provides a guide for future structure optimization.

Reviews citing this publication (1)

  1. Development of nitric oxide synthase inhibitors for neurodegeneration and neuropathic pain. Mukherjee P, Cinelli MA, Kang S, Silverman RB. Chem Soc Rev 43 6814-6838 (2014)

Articles citing this publication (3)

  1. An Accessible Chiral Linker to Enhance Potency and Selectivity of Neuronal Nitric Oxide Synthase Inhibitors. Jing Q, Li H, Roman LJ, Martásek P, Poulos TL, Silverman RB. ACS Med Chem Lett 5 56-60 (2014)
  2. Combination of chiral linkers with thiophenecarboximidamide heads to improve the selectivity of inhibitors of neuronal nitric oxide synthase. Jing Q, Li H, Roman LJ, Martásek P, Poulos TL, Silverman RB. Bioorg. Med. Chem. Lett. 24 4504-4510 (2014)
  3. Inhibitor Bound Crystal Structures of Bacterial Nitric Oxide Synthase. Holden JK, Dejam D, Lewis MC, Huang H, Kang S, Jing Q, Xue F, Silverman RB, Poulos TL. Biochemistry 54 4075-4082 (2015)