title: Low brain penetrant CB1 receptor agonists for the treatment of neuropathic pain.
abstract: Novel, low brain penetrant, orally bioavailable CB1 receptor agonists were designed starting from a mature lead series of potent brain penetrant CB1 receptor agonists. Increasing the calculated polar surface area was found to be a good strategy for reducing brain penetration whilst retaining drug-like properties. This in silico approach led to the discovery of LBP1, an orally bioavailable, low brain penetrant CB1 receptor agonist with robust activity in rodent models of neuropathic pain and a good preclinical therapeutic profile, which was selected for clinical development.
authors.affiliation: Department of Chemistry, Merck Research Laboratories, MSD, Newhouse, Lanarkshire, UK. julia1adam@gmail.com
authors.forename: Julia M
authors.initials: JM
authors.lastname: Adam
authors.forename: John K
authors.initials: JK
authors.lastname: Clark
authors.forename: Keneth
authors.initials: K
authors.lastname: Davies
authors.forename: Kathryn
authors.initials: K
authors.lastname: Everett
authors.forename: Ruth
authors.initials: R
authors.lastname: Fields
authors.forename: Stuart
authors.initials: S
authors.lastname: Francis
authors.forename: Fiona
authors.initials: F
authors.lastname: Jeremiah
authors.forename: Takao
authors.initials: T
authors.lastname: Kiyoi
authors.forename: Maurice
authors.initials: M
authors.lastname: Maidment
authors.forename: Angus
authors.initials: A
authors.lastname: Morrison
authors.forename: Paul
authors.initials: P
authors.lastname: Ratcliffe
authors.forename: Alan
authors.initials: A
authors.lastname: Prosser
authors.forename: Jurgen
authors.initials: J
authors.lastname: Schulz
authors.forename: Grant
authors.initials: G
authors.lastname: Wishart
authors.forename: James
authors.initials: J
authors.lastname: Baker
authors.forename: Susan
authors.initials: S
authors.lastname: Boyce
authors.forename: Robert
authors.initials: R
authors.lastname: Campbell
authors.forename: Jean E
authors.initials: JE
authors.lastname: Cottney
authors.forename: Maureen
authors.initials: M
authors.lastname: Deehan
authors.forename: Iain
authors.initials: I
authors.lastname: Martin
mesh_terms: D000818:Animals; D001921:Brain / Q000098:blood supply / Q000378:metabolism; D018938:Caco-2 Cells; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051379:Mice; D009437:Neuralgia / Q000188:drug therapy*; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists*
chemical_list: D007211:Indoles; C574960:LBP1 compound; D010069:Oxadiazoles; D043884:Receptor, Cannabinoid, CB1