title: Design, synthesis and evaluation of N-[(3S)-pyrrolidin-3-yl]benzamides as selective noradrenaline reuptake inhibitors: CNS penetration in a more polar template.
abstract: Derivatives of N-[(3S)-pyrrolidin-3-yl]benzamides are disclosed as a new series of noradrenaline reuptake inhibitors (NRI). Structure-activity relationships established that potent NRI activity could be achieved by appropriate substitution at the 2-position of the phenyl ring; consequently, selective NRIs and dual NSRIs were prepared. Benzamide 11e was identified as a potent NRI with good selectivity over SRI and DRI, good in vitro metabolic stability, weak CYP inhibition and low affinity for ion channels. Evaluation in vivo, in rat microdialysis experiments, showed 11e increased noradrenaline levels by up to 350% confirming good CNS penetration. Benzamide 11e was differentiated from previous NRIs as it was significantly less lipophilic (DeltaclogP -0.9).
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: Florian
authors.initials: F
authors.lastname: Wakenhut
authors.forename: Thomas
authors.initials: T
authors.lastname: Ryckmans
authors.forename: Alan
authors.initials: A
authors.lastname: Stobie
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002490:Central Nervous System / Q000378:metabolism*; D002491:Central Nervous System Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism*; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats
chemical_list: D018759:Adrenergic Uptake Inhibitors; D001549:Benzamides; D002491:Central Nervous System Agents; C543938:N-((3S)-pyrrolidin-3-yl)benzamide; D011759:Pyrrolidines; D009638:Norepinephrine