First-in-class, dual-action, 3,5-disubstituted indole derivatives having human nitric oxide synthase (nNOS) and norepinephrine reuptake inhibitory (NERI) activity for the treatment of neuropathic pain

Gabriela Mladenova; Subhash C Annedi; Jailall Ramnauth; Shawn P Maddaford; Suman Rakhit; John S Andrews; Dongqin Zhang; Frank Porreca

doi:10.1021/jm300138g

First-in-class, dual-action, 3,5-disubstituted indole derivatives having human nitric oxide synthase (nNOS) and norepinephrine reuptake inhibitory (NERI) activity for the treatment of neuropathic pain

J Med Chem. 2012 Apr 12;55(7):3488-501. doi: 10.1021/jm300138g. Epub 2012 Apr 4.

Authors

Gabriela Mladenova¹, Subhash C Annedi, Jailall Ramnauth, Shawn P Maddaford, Suman Rakhit, John S Andrews, Dongqin Zhang, Frank Porreca

Affiliation

¹ NeurAxon Inc., 2395 Speakman Drive, Suite 1001, Mississauga, Ontario L5K 1B3, Canada. gmladenova@neuraxon.com

PMID: 22420844
DOI: 10.1021/jm300138g

Abstract

A family of different 3,5-disubstituted indole derivatives having 6-membered rings were designed, synthesized, and demonstrated inhibition of human nitric oxide synthase (NOS) with norepinephrine reuptake inhibitory activity (NERI). The structure-activity relationship (SAR) within the cyclohexane ring showed the cis-isomers to be more potent for neuronal NOS and selective over endothelial NOS compared to their trans-counterparts. Compounds, such as cis-(+)-37, exhibited dual nNOS and NET inhibition (IC(50) of 0.56 and 1.0 μM, respectively) and excellent selectivity (88-fold and 12-fold) over eNOS and iNOS, respectively. The lead compound (cis-(+)-37) showed lack of any direct vasoconstriction or inhibition of ACh-mediated vasorelaxation in isolated human coronary arteries. Additionally, cis-(+)-37 was effective at reversing both allodynia and thermal hyperalgesia in a standard Chung (spinal nerve ligation) rat neuropathic pain model. Overall, the data suggest that cis-(+)-37 is a promising dual action development candidate having therapeutic potential for the treatment of neuropathic pain.

MeSH terms

Adrenergic Uptake Inhibitors / chemical synthesis*
Adrenergic Uptake Inhibitors / chemistry
Adrenergic Uptake Inhibitors / pharmacology
Analgesics / chemical synthesis*
Analgesics / chemistry
Analgesics / pharmacology
Animals
CHO Cells
Coronary Vessels / drug effects
Coronary Vessels / physiology
Cricetinae
Cricetulus
Cyclohexanes / chemical synthesis
Cyclohexanes / chemistry
Cyclohexanes / pharmacology
ERG1 Potassium Channel
Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
HEK293 Cells
High-Throughput Screening Assays
Humans
In Vitro Techniques
Indoles / chemical synthesis*
Indoles / chemistry
Indoles / pharmacology
Muscle Contraction
Muscle, Smooth, Vascular / drug effects
Muscle, Smooth, Vascular / physiology
Neuralgia / drug therapy*
Nitric Oxide Synthase Type I / antagonists & inhibitors*
Norepinephrine Plasma Membrane Transport Proteins / metabolism*
Rats
Stereoisomerism
Structure-Activity Relationship
Thiophenes / chemical synthesis*
Thiophenes / chemistry
Thiophenes / pharmacology
Vascular Resistance

Substances

Adrenergic Uptake Inhibitors
Analgesics
Cyclohexanes
ERG1 Potassium Channel
Ether-A-Go-Go Potassium Channels
Indoles
N-(3-(3-(methylamino)cyclohexyl)-1H-indol-5-yl)thiophene-2-carboximidamide
Norepinephrine Plasma Membrane Transport Proteins
Thiophenes
Nitric Oxide Synthase Type I