title: Derivatives of (3S)-N-(biphenyl-2-ylmethyl)pyrrolidin-3-amine as selective noradrenaline reuptake inhibitors: Reducing P-gp mediated efflux by modulation of H-bond acceptor capacity.
abstract: Derivatives of (3S)-N-(biphenyl-2-ylmethyl)pyrrolidin-3-amine are disclosed as a new series of noradrenaline reuptake inhibitors (NRI). Carboxamide 9e, carbamate 11b and sulfonamide 13a were identified as potent NRIs with excellent selectivity over SRI and DRI, good in vitro metabolic stability and weak CYP inhibition. Carbamate 11b demonstrated superior transit performance in MDCK-mdr1 cell lines with minimal P-gp efflux which was attributed to reduced HBA capacity of the carbamate group. Evaluation in vivo, in rat microdialysis experiments, showed 11b increased noradrenaline levels by 400% confirming good CNS penetration.
authors.affiliation: Discovery Chemistry, Pfizer Global Research and Development, Sandwich Laboratories, Sandwich, Kent CT13 9NJ, UK. paul.fish@pfizer.com
authors.forename: Paul V
authors.initials: PV
authors.lastname: Fish
authors.forename: Nancy S
authors.initials: NS
authors.lastname: Barta
authors.forename: David L F
authors.initials: DL
authors.lastname: Gray
authors.forename: Thomas
authors.initials: T
authors.lastname: Ryckmans
authors.forename: Alan
authors.initials: A
authors.lastname: Stobie
authors.forename: Florian
authors.initials: F
authors.lastname: Wakenhut
authors.forename: Gavin A
authors.initials: GA
authors.lastname: Whitlock
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000187:drug effects; D020650:Combinatorial Chemistry Techniques; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism
chemical_list: D011759:Pyrrolidines; D017367:Selective Serotonin Reuptake Inhibitors; C530668:PF-3609113