title: 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.
abstract: 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 (Ki= 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-HT2Areceptor. 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-HT2Areceptors 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.
authors.affiliation: Discovery Research, Suven Life Sciences Ltd , Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad 500 034, India.
authors.forename: Ramakrishna
authors.identifier: 0000-0002-2045-0784
authors.initials: R
authors.lastname: Nirogi
authors.affiliation: Discovery Research, Suven Life Sciences Ltd , Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad 500 034, India.
authors.forename: Anil
authors.initials: A
authors.lastname: Shinde
authors.affiliation: Discovery Research, Suven Life Sciences Ltd , Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad 500 034, India.
authors.forename: Rama Sastry
authors.initials: RS
authors.lastname: Kambhampati
authors.affiliation: Discovery Research, Suven Life Sciences Ltd , Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad 500 034, India.
authors.forename: Abdul Rasheed
authors.initials: AR
authors.lastname: Mohammed
authors.affiliation: Discovery Research, Suven Life Sciences Ltd , Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad 500 034, India.
authors.forename: Sangram Keshari
authors.initials: SK
authors.lastname: Saraf
authors.affiliation: Discovery Research, Suven Life Sciences Ltd , Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad 500 034, India.
authors.forename: Rajesh Kumar
authors.initials: RK
authors.lastname: Badange
authors.affiliation: Discovery Research, Suven Life Sciences Ltd , Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad 500 034, India.
authors.forename: Thrinath Reddy
authors.initials: TR
authors.lastname: Bandyala
authors.affiliation: Discovery Research, Suven Life Sciences Ltd , Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad 500 034, India.
authors.forename: Venugopalarao
authors.initials: V
authors.lastname: Bhatta
authors.affiliation: Discovery Research, Suven Life Sciences Ltd , Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad 500 034, India.
authors.forename: Kumar
authors.initials: K
authors.lastname: Bojja
authors.affiliation: Discovery Research, Suven Life Sciences Ltd , Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad 500 034, India.
authors.forename: Veena
authors.initials: V
authors.lastname: Reballi
authors.affiliation: Discovery Research, Suven Life Sciences Ltd , Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad 500 034, India.
authors.forename: Ramkumar
authors.initials: R
authors.lastname: Subramanian
authors.affiliation: Discovery Research, Suven Life Sciences Ltd , Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad 500 034, India.
authors.forename: Vijay
authors.initials: V
authors.lastname: Benade
authors.affiliation: Discovery Research, Suven Life Sciences Ltd , Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad 500 034, India.
authors.forename: Raghava Choudary
authors.initials: RC
authors.lastname: Palacharla
authors.affiliation: Discovery Research, Suven Life Sciences Ltd , Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad 500 034, India.
authors.forename: Gopinadh
authors.initials: G
authors.lastname: Bhyrapuneni
authors.affiliation: Discovery Research, Suven Life Sciences Ltd , Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad 500 034, India.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Jayarajan
authors.affiliation: Discovery Research, Suven Life Sciences Ltd , Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad 500 034, India.
authors.forename: Vinod
authors.initials: V
authors.lastname: Goyal
authors.affiliation: Discovery Research, Suven Life Sciences Ltd , Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad 500 034, India.
authors.forename: Venkat
authors.initials: V
authors.lastname: Jasti
mesh_terms: D000284:Administration, Oral; D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D055808:Drug Discovery; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D010879:Piperazines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D007211:Indoles; D010879:Piperazines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C097216:serotonin 6 receptor; C000621657:1-((2-bromophenyl)sulfonyl)-5-methoxy-3-((4-methyl-1-piperazinyl)methyl)-1H-indole dimesylate monohydrate