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.

Department of Biochemistry The University of Texas Health Science Center San Antonio TX 78384 7760 USA

Department of Biochemistry The University of Texas Health Science Center San Antonio TX 78384 7760 USA; Department of Pediatrics and Center for Applied Genomics 1st School of Medicine Charles University Prague Czech Republic

Department of Chemistry Northwestern University 2145 Sheridan Road Evanston IL 60208 3113 USA; Department of Molecular Biosciences Northwestern University 2145 Sheridan Road Evanston IL 60208 3113 USA; Chemistry of Life Processes Institute Northwestern University 2145 Sheridan Road Evanston IL 60208 3113 USA; Center for Molecular Innovation and Drug Discovery Northwestern University 2145 Sheridan Road Evanston IL 60208 3113 USA

Department of Molecular Biology and Biochemistry University of California Irvine CA 92697 USA; Department of Pharmaceutical Chemistry University of California Irvine CA 92697 USA; Department of Chemistry University of California Irvine CA 92697 USA

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Mustafa AK, Gadalla MM, Synder SH. Sci. Signal. 2009;2:1. PubMed PMC

Vallance P, Leiper J. Nature Rev. Drug Discovery. 2002;1:939. PubMed

Sims NR, Anderson MF. Neurochem. Int. 2002;40:511. PubMed

Miclescu A, Gordh T. Acta Anaesthesiol. Scand. 2009;53:1107. PubMed

Calabrese V, Mancuso C, Calvani M, Rizzarelli E, Butterfield AD, Stella AMG. Nature Rev. Neurosci. 2007;8:766. PubMed

Zhang L, Dawson VL, Dawson TM. Pharmacol. Ther. 2006;109:33. PubMed

Dorheim M-A, Tracey WR, Pollock JS, Grammas P. Biochem. Biophys. Res. Commun. 1994;205:659. PubMed

Norris PJ, Waldvogel HJ, Faull RLM, Love DR, Emson PC. Neuronsicence. 1996;72:1037. PubMed

Cayatte AJ, Palacino JJ, Horten K, Cohen RA. Arterioscler. Thromb. 1994;14:753. PubMed

Maddaford S, Annedi SC, Ramnauth J, Rakhit S. Annu. Rep. Med. Chem. 2009;44:27.

Narayanan K, Spack L, McMillan K, Kilbourn RG, Hayward MA, Masters BSS, Griffith OW. J. Biol. Chem. 1995;270:11103. PubMed

Ji H, Erdal EP, Litzinger EA, Seo J, Zhu Y, Xue F, Fang J, Huang J, Silverman RB. Reitz AB, Choudhary MI, Atta-ur-Rahman, editors. In Frontiers in Medicinal Chemistry. Bentham Science. 2009;54:842.

Ijuin R, Umezawa N, Nagai S, Higuchi T. Bioorg. Med. Chem. Lett. 2005;15:2881. PubMed

Ji H, Gomez-Vidal JA, Martásek P, Roman LJ, Silverman RB. J. Med. Chem. 2006;49:6254. PubMed PMC

Ramnauth J, Speed J, Maddaford SP, Dove P, Annedi SC, Renton P, Rakhit S, Andrews J, Silverman S, Mladenova G, Zinghini S, Nair S, Catalano C, Lee DKH, Felice MD, Porreca FJ. Med. Chem. 2011;54:5562. PubMed PMC

Annedi SC, Ramnauth J, Maddaford SP, Renton P, Rakhit S, Mladenova G, Dove P, Silverman S, Andrews JS, Felice MD, Porreca F. J. Med. Chem. 2012;55:943. PubMed

Liang G, Neuenschwander K, Chen X, Wei L, Munson R, Francisco G, Scotese A, Shutske G, Black M, Sarhan S, Jiang J, Morize I, Vaz RJ. Med. Chem. Commun. 2011;2:201.

Silverman RB. Acc. Chem. Res. 2009;42:439. PubMed PMC

Jing Q, Li H, Chreifi G, Roman LJ, Martásek P, Poulos TL, Silverman RB. Bioorg. Med. Chem. Lett. 2013;23:5674. PubMed PMC

Jing Q, Li H, Roman LJ, Martásek P, Poulos TL, Silverman RB. ACS MedChemLett. 2014;5:56. PubMed PMC

Zhang ZG, Reif D, Macdonald J, Tang WX, Kamp DK, Gentile RJ, Shakespeare WC, Murray RJ, Chopp MJ. Cereb. Blood Flow Metab. 1996;16:599. PubMed

Salerno L, Sorrenti V, Di Giacomo C, Romeo G, Siracusa MA. Curr. Pharm. Des. 2002;8:177. PubMed

Kang S, Tang W, Li H, Chreifi G, Martásek P, Roman LJ, Poulos TL, Silverman RB. J. Med. Chem. 2014;57:4382. PubMed PMC