Novel selective inhibitors of neutral endopeptidase for the treatment of female sexual arousal disorder.
A series of substituted glutaramides were synthesised using Candoxatrilat 1 as a lead and evaluated for potency against neutral endopeptidase (NEP) as a potential treatment for female sexual arousal disorder (FSAD). In this paper, we describe studies in which we were able to increase NEP activity substantially over the levels reported for previous compounds from this programme by appropriate substitution in both the P(1)(') and P(2)(') regions. Optimisation led to the 4-chlorophenpropylamide S-30 which was selected as a candidate for further study.
Pryde
David C
DC
Department of Discovery Chemistry, Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK. David.Pryde@Pfizer.com
Cook
Andrew S
AS
Burring
Denise J
DJ
Jones
Lyn H
LH
Foll
Stephanie
S
Platts
Michelle Y
MY
Sanderson
Vivienne
V
Corless
Martin
M
Stobie
Alan
A
Middleton
Donald S
DS
Foster
Laura
L
Barker
Laura
L
Van Der Graaf
Piet
P
Stacey
Peter
P
Kohl
Christopher
C
Coggon
Sara
S
Beaumont
Kevin
K
D000818:Animals; D003509:Cyclohexanecarboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry* / Q000493:pharmacokinetics; D004285:Dogs; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D015394:Molecular Structure; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry* / Q000493:pharmacokinetics; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D020018:Sexual Dysfunctions, Psychological / Q000188:drug therapy*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013552:Swine
D003509:Cyclohexanecarboxylic Acids; D011480:Protease Inhibitors; C060942:candoxatrilat; D015260:Neprilysin