Combination of chiral linkers with thiophenecarboximidamide heads to improve the selectivity of inhibitors of neuronal nitric oxide synthase

Qing Jing; Huiying Li; Linda J Roman; Pavel Martásek; Thomas L Poulos; Richard B Silverman

doi:10.1016/j.bmcl.2014.07.079

Combination of chiral linkers with thiophenecarboximidamide heads to improve the selectivity of inhibitors of neuronal nitric oxide synthase

Bioorg Med Chem Lett. 2014 Sep 15;24(18):4504-4510. doi: 10.1016/j.bmcl.2014.07.079. Epub 2014 Aug 12.

Authors

Qing Jing¹, Huiying Li², Linda J Roman³, Pavel Martásek⁴, Thomas L Poulos⁵, Richard B Silverman⁶

Affiliations

¹ 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.
² 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.
³ Department of Biochemistry, The University of Texas Health Science Center, San Antonio, TX 78384-7760, USA.
⁴ 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.
⁵ 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. Electronic address: poulos@uci.edu.
⁶ 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. Electronic address: Agman@chem.northwestern.edu.

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.

Keywords: Heme; Nitric oxide synthase; Protein crystallography; Selective inhibition; Tetrahydrobiopterin; Thiophenecarboximidamide.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Imides / chemical synthesis
Imides / chemistry
Imides / pharmacology*
Models, Molecular
Molecular Structure
Nitric Oxide Synthase Type I / antagonists & inhibitors*
Nitric Oxide Synthase Type I / metabolism
Structure-Activity Relationship
Thiophenes / chemical synthesis
Thiophenes / chemistry
Thiophenes / pharmacology*

Substances

Enzyme Inhibitors
Imides
Thiophenes
Nitric Oxide Synthase Type I

Abstract

Publication types

MeSH terms

Substances

Grants and funding