Novel selective inhibitors of neutral endopeptidase for the treatment of female sexual arousal disorder. Synthesis and activity of functionalized glutaramides.
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)
Pryde
David C
DC
Department of Discovery Chemistry, Pfizer Global Research and Development, Sandwich, Kent CT13 9NJ, UK. David.Pryde@pfizer.com
Maw
Graham N
GN
Planken
Simon
S
Platts
Michelle Y
MY
Sanderson
Vivienne
V
Corless
Martin
M
Stobie
Alan
A
Barber
Christopher G
CG
Russell
Rachel
R
Foster
Laura
L
Barker
Laura
L
Wayman
Christopher
C
Van Der Graaf
Piet
P
Stacey
Peter
P
Morren
Debbie
D
Kohl
Christopher
C
Beaumont
Kevin
K
Coggon
Sara
S
Tute
Michael
M
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
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