title: Novel selective inhibitors of neutral endopeptidase for the treatment of female sexual arousal disorder. Synthesis and activity of functionalized glutaramides.
abstract: Female sexual arousal disorder (FSAD) is a highly prevalent sexual disorder affecting up to 40% of women. We describe herein our efforts to identify a selective neutral endopeptidase (NEP) inhibitor as a potential treatment for FSAD. The rationale for this approach, together with a description of the medicinal chemistry strategy, lead compounds, and SAR investigations are detailed. In particular, the strategy of starting with the clinically precedented selective NEP inhibitor, Candoxatrilat, and targeting low molecular weight and relatively polar mono-carboxylic acids is described. This led ultimately to the prototype development candidate R-13, for which detailed pharmacology and pharmacokinetic parameters are presented.(1)
authors.affiliation: Department of Discovery Chemistry, Pfizer Global Research and Development, Sandwich, Kent CT13 9NJ, UK. David.Pryde@pfizer.com
authors.forename: David C
authors.initials: DC
authors.lastname: Pryde
authors.forename: Graham N
authors.initials: GN
authors.lastname: Maw
authors.forename: Simon
authors.initials: S
authors.lastname: Planken
authors.forename: Michelle Y
authors.initials: MY
authors.lastname: Platts
authors.forename: Vivienne
authors.initials: V
authors.lastname: Sanderson
authors.forename: Martin
authors.initials: M
authors.lastname: Corless
authors.forename: Alan
authors.initials: A
authors.lastname: Stobie
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Barber
authors.forename: Rachel
authors.initials: R
authors.lastname: Russell
authors.forename: Laura
authors.initials: L
authors.lastname: Foster
authors.forename: Laura
authors.initials: L
authors.lastname: Barker
authors.forename: Christopher
authors.initials: C
authors.lastname: Wayman
authors.forename: Piet
authors.initials: P
authors.lastname: Van Der Graaf
authors.forename: Peter
authors.initials: P
authors.lastname: Stacey
authors.forename: Debbie
authors.initials: D
authors.lastname: Morren
authors.forename: Christopher
authors.initials: C
authors.lastname: Kohl
authors.forename: Kevin
authors.initials: K
authors.lastname: Beaumont
authors.forename: Sara
authors.initials: S
authors.lastname: Coggon
authors.forename: Michael
authors.initials: M
authors.lastname: Tute
mesh_terms: D000146:Acids, Carbocyclic / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000577:Amides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D002987:Clitoris / Q000098:blood supply / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D005260:Female; D006801:Humans; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D010421:Pentanoic Acids / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D012039:Regional Blood Flow / Q000187:drug effects; D020018:Sexual Dysfunctions, Psychological / Q000188:drug therapy*; D013045:Species Specificity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014621:Vagina / Q000098:blood supply / Q000187:drug effects
chemical_list: C513162:2-(1-((2-ethyl-1,3,4-thiadiazol-5-yl)aminocarbonyl)cyclopentyl)pentanoic acid; D000146:Acids, Carbocyclic; D000577:Amides; D010421:Pentanoic Acids; D011725:Pyridines; D011994:Recombinant Proteins; D013830:Thiadiazoles; D015260:Neprilysin