N-[(3S)-Pyrrolidin-3-yl]benzamides as novel dual serotonin and noradrenaline reuptake inhibitors: impact of small structural modifications on P-gp recognition and CNS penetration.
The structure-activity relationship and the synthesis of novel N-[(3S)-pyrrolidin-3-yl]benzamides as dual serotonin and noradrenaline monoamine reuptake inhibitors (SNRI) is described. Preferred compound 9 aka PF-184,298 is a potent SNRI with good selectivity over dopamine reuptake inhibition (DRI), good in vitro metabolic stability, weak CYP inhibition and drug-like physicochemical properties consistent with CNS target space. Evaluation in an in vivo preclinical model of stress urinary incontinence showed 9 significantly increased urethral tone at free plasma concentrations consistent with its in vitro primary pharmacology.
Wakenhut
Florian
F
Department of Genitourinary Chemistry, Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich, Kent, UK. florian.wakenhut@pfizer.com
Allan
Gill A
GA
Fish
Paul V
PV
Fray
M Jonathan
MJ
Harrison
Anthony C
AC
McCoy
Rachel
R
Phillips
Stephen C
SC
Ryckmans
Thomas
T
Stobie
Alan
A
Westbrook
Dominique
D
Westbrook
Simon L
SL
Whitlock
Gavin A
GA
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D018759:Adrenergic Uptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000813:Anilides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D002460:Cell Line; D002490:Central Nervous System / Q000378:metabolism*; D004285:Dogs; D018765:Dopamine Uptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D009638:Norepinephrine / Q000378:metabolism; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018759:Adrenergic Uptake Inhibitors; D000813:Anilides; D001549:Benzamides; D018765:Dopamine Uptake Inhibitors; D009638:Norepinephrine; D011759:Pyrrolidines; D017367:Selective Serotonin Reuptake Inhibitors; C544972:PF 184,298