title: Optimisation of in silico derived 2-aminobenzimidazole hits as unprecedented selective kappa opioid receptor agonists.
abstract: Kappa opioid receptor (KOR) is an important mediator of pain signaling and it is targeted for the treatment of various pains. Pharmacophore based mining of databases led to the identification of 2-aminobenzimidazole derivative as KOR agonists with selectivity over the other opioid receptors DOR and MOR. A short SAR exploration with the objective of identifying more polar and hence less brain penetrant agonists is described herewith. Modeling studies of the recently published structures of KOR, DOR and MOR are used to explain the receptor selectivity. The synthesis, biological evaluation and SAR of novel benzimidazole derivatives as KOR agonists are described. The in vivo proof of principle for anti-nociceptive effect with a lead compound from this series is exemplified.
authors.affiliation: Discovery Research, Dr. Reddy's Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500049, India. Electronic address: pradipks@drreddys.com.
authors.forename: Pradip K
authors.initials: PK
authors.lastname: Sasmal
authors.affiliation: Discovery Research, Dr. Reddy's Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500049, India.
authors.forename: C Vamsee
authors.initials: CV
authors.lastname: Krishna
authors.affiliation: Discovery Research, Dr. Reddy's Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500049, India.
authors.forename: S Sudheerkumar
authors.initials: SS
authors.lastname: Adabala
authors.affiliation: Discovery Research, Dr. Reddy's Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500049, India.
authors.forename: M
authors.initials: M
authors.lastname: Roshaiah
authors.affiliation: Discovery Research, Dr. Reddy's Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500049, India.
authors.forename: Khaji Abdul
authors.initials: KA
authors.lastname: Rawoof
authors.affiliation: Discovery Research, Dr. Reddy's Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500049, India.
authors.forename: Emima
authors.initials: E
authors.lastname: Thadi
authors.affiliation: Discovery Research, Dr. Reddy's Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500049, India.
authors.forename: K Pavan
authors.initials: KP
authors.lastname: Sukumar
authors.affiliation: Discovery Research, Dr. Reddy's Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500049, India.
authors.forename: Srisailam
authors.initials: S
authors.lastname: Cheera
authors.affiliation: Discovery Research, Dr. Reddy's Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500049, India.
authors.forename: Chandrasekhar
authors.initials: C
authors.lastname: Abbineni
authors.affiliation: Discovery Research, Dr. Reddy's Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500049, India.
authors.forename: K V L Narasimha
authors.initials: KV
authors.lastname: Rao
authors.affiliation: Discovery Research, Dr. Reddy's Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500049, India.
authors.forename: A
authors.initials: A
authors.lastname: Prasanthi
authors.affiliation: Discovery Research, Dr. Reddy's Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500049, India.
authors.forename: Kamal
authors.initials: K
authors.lastname: Nijhawan
authors.affiliation: Discovery Research, Dr. Reddy's Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500049, India.
authors.forename: Mahaboobi
authors.initials: M
authors.lastname: Jaleel
authors.affiliation: Discovery Research, Dr. Reddy's Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500049, India.
authors.forename: Lakshmi Ramachandran
authors.initials: LR
authors.lastname: Iyer
authors.affiliation: Discovery Research, Dr. Reddy's Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500049, India.
authors.forename: T Krishna
authors.initials: TK
authors.lastname: Chaitanya
authors.affiliation: Discovery Research, Dr. Reddy's Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500049, India.
authors.forename: Nirbhay Kumar
authors.initials: NK
authors.lastname: Tiwari
authors.affiliation: Discovery Research, Dr. Reddy's Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500049, India.
authors.forename: N Lavanya
authors.initials: NL
authors.lastname: Krishna
authors.affiliation: Discovery Research, Dr. Reddy's Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500049, India.
authors.forename: Vijay
authors.initials: V
authors.lastname: Potluri
authors.affiliation: Discovery Research, Dr. Reddy's Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500049, India.
authors.forename: Ish
authors.initials: I
authors.lastname: Khanna
authors.affiliation: 7TM Pharma A/S, Fremtidsvej 3, DK-2970 Hørsholm, Denmark; NNF, Center for Protein Research and NNF Center for Basic Metabolic Research, University of Copenhagen, Denmark.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Frimurer
authors.affiliation: NNF, Center for Protein Research and NNF Center for Basic Metabolic Research, University of Copenhagen, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Lückmann
authors.affiliation: 7TM Pharma A/S, Fremtidsvej 3, DK-2970 Hørsholm, Denmark.
authors.forename: Øystein
authors.initials: Ø
authors.lastname: Rist
authors.affiliation: 7TM Pharma A/S, Fremtidsvej 3, DK-2970 Hørsholm, Denmark.
authors.forename: Lisbeth
authors.initials: L
authors.lastname: Elster
authors.affiliation: 7TM Pharma A/S, Fremtidsvej 3, DK-2970 Hørsholm, Denmark. Electronic address: thomas.hogberg@leo-pharma.com.
authors.forename: Thomas
authors.initials: T
authors.lastname: Högberg
mesh_terms: D000595:Amino Acid Sequence; D001562:Benzimidazoles / Q000494:pharmacology*; D003198:Computer Simulation; D006801:Humans; D008969:Molecular Sequence Data; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; D017473:Receptors, Opioid, kappa; C027391:2-aminobenzimidazole
keywords: Anti-nociception; Benzimidazoles; KOR agonists; Kappa opioid receptor (KOR)