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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)
Related entries: 4upm, 4upo, 4upp, 4upq, 4upr, 4ups, 4upt

Cited: 5 times
EuropePMC logo PMID: 25149509

Abstract

To develop potent and selective nNOS inhibitors, a new series of double-headed molecules with chiral linkers that derive from natural amino acid derivatives have been designed and synthesized. The new structures integrate a thiophenecarboximidamide head with two types of chiral linkers, presenting easy synthesis and good inhibitory properties. Inhibitor (S)-9b exhibits a potency of 14.7 nM against nNOS and is 1134 and 322-fold more selective for nNOS over eNOS and iNOS, respectively. Crystal structures show that the additional binding between the aminomethyl moiety of 9b and propionate A on the heme and tetrahydrobiopterin (H4B) in nNOS, but not eNOS, contributes to its high selectivity. This work demonstrates the advantage of integrating known structures into structure optimization, and it should be possible to more readily develop compounds that incorporate bioavailability with these advanced features. Moreover, this integrative strategy is a general approach in new drug discovery.

Articles - 4upn mentioned but not cited (2)

  1. 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)
  2. 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)


Reviews citing this publication (1)

  1. Nitric oxide synthase and structure-based inhibitor design. Poulos TL, Li H. Nitric Oxide 63 68-77 (2017)

Articles citing this publication (2)

  1. 2-Aminopyridines with a Truncated Side Chain To Improve Human Neuronal Nitric Oxide Synthase Inhibitory Potency and Selectivity. Kang S, Li H, Tang W, Martásek P, Roman LJ, Poulos TL, Silverman RB. J. Med. Chem. 58 5548-5560 (2015)
  2. Nitric Oxide Synthase as a Target for Methicillin-Resistant Staphylococcus aureus. Holden JK, Kang S, Beasley FC, Cinelli MA, Li H, Roy SG, Dejam D, Edinger AL, Nizet V, Silverman RB, Poulos TL. Chem. Biol. 22 785-792 (2015)


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