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 |
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Authors: | Fish Paul V Barta Nancy S Gray David L F Ryckmans Thomas Stobie Alan Wakenhut Florian Whitlock Gavin A |
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Institution: | aDiscovery Chemistry, Pfizer Global Research and Development, Sandwich Laboratories, Sandwich, Kent CT13 9NJ, UK;bDiscovery Chemistry, Pfizer Global Research and Development, Ann Arbor Laboratories, Ann Arbor, MI 48105, USA |
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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. |
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Keywords: | Noradrenaline reuptake inhibitor NRI Carbamate H-bond acceptor capacity CNS penetration |
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