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

• Published in: Journal of medicinal chemistry Vol. 55; no. 7; pp. 3488 - 3501
• Main Authors: Mladenova, Gabriela, Annedi, Subhash C, Ramnauth, Jailall, Maddaford, Shawn P, Rakhit, Suman, Andrews, John S, Zhang, Dongqin, Porreca, Frank
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 12.04.2012; Amer Chemical Soc
• Subjects: Adrenergic Uptake Inhibitors - chemical synthesis; Adrenergic Uptake Inhibitors - chemistry; Adrenergic Uptake Inhibitors - pharmacology; Analgesics - chemical synthesis; Analgesics - chemistry; Analgesics - pharmacology; Animals; Chemistry, Medicinal; 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; Life Sciences & Biomedicine; 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; Pharmacology & Pharmacy; Rats; Science & Technology; Stereoisomerism; Structure-Activity Relationship; Thiophenes - chemical synthesis; Thiophenes - chemistry; Thiophenes - pharmacology; Vascular Resistance; SELECTIVE INHIBITOR; ANTIDEPRESSANTS; ADJUVANT ANALGESICS; DULOXETINE; CHEMICAL-SHIFTS; DOUBLE-BLIND; SEROTONIN; NORADRENALINE; PATHOPHYSIOLOGY; PREDICTION
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm300138g

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 (IC50 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.