Discovery and Development of 1‑[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]‑1H‑indole Dimesylate Monohydrate (SUVN-502): A Novel, Potent, Selective and Orally Active Serotonin 6 (5-HT6) Receptor Antagonist for Potential Treatment of Alzheimer’s Disease

• Published in: Journal of medicinal chemistry 2017-03, Vol.60 (5), p.1843-1859
• Main Authors: Nirogi, Ramakrishna, Shinde, Anil, Kambhampati, Rama Sastry, Mohammed, Abdul Rasheed, Saraf, Sangram Keshari, Badange, Rajesh kumar, Bandyala, Thrinath Reddy, Bhatta, Venugopalarao, Bojja, Kumar, Reballi, Veena, Subramanian, Ramkumar, Benade, Vijay, Palacharla, Raghava Choudary, Bhyrapuneni, Gopinadh, Jayarajan, Pradeep, Goyal, Vinod, Jasti, Venkat
• Format: Article
• Language: English
• Subjects: Administration, Oral; Alzheimer Disease - drug therapy; Animals; Drug Discovery; Humans; Indoles - administration & dosage; Indoles - chemistry; Indoles - pharmacokinetics; Indoles - pharmacology; Male; Piperazines - administration & dosage; Piperazines - chemistry; Piperazines - pharmacokinetics; Piperazines - pharmacology; Rats; Rats, Wistar; Receptors, Serotonin - drug effects; Serotonin Antagonists - pharmacokinetics; Serotonin Antagonists - pharmacology; Serotonin Antagonists - therapeutic use
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.6b01662

Optimization of a novel series of 3-(piperazinylmethyl) indole derivatives as 5-hydroxytryptamine-6 receptor (5-HT6R) antagonists resulted in identification of 1-[(2-bromophenyl)­sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)­methyl]-1H-indole dimesylate monohydrate (5al, SUVN-502) as a clinical candidate for potential treatment of cognitive disorders. It has high affinity at human 5-HT6R (K i = 2.04 nM) and selectivity over 100 target sites which include receptors, enzymes, peptides, growth factors, ion channels, steroids, immunological factors, second messengers, and prostaglandins. It has high selectivity over 5-HT2A receptor. It is orally bioavailable and brain penetrant with robust preclinical efficacy. The combination of 5al, donepezil, and memantine (triple combination) produces synergistic effects in extracellular levels of acetylcholine in the ventral hippocampus. Preclinical efficacy in triple combination and high selectivity over 5-HT2A receptors are the differentiating features which culminated in selection of 5al for further development. The Phase-1 evaluation of safety and pharmacokinetics has been completed, allowing for the initiation of a Phase-2 proof of concept study.