The discovery of small molecule inhibitors of neutral endopeptidase. Structure-activity studies on functionalized glutaramides.
A series of small molecule glutaramides were synthesized and evaluated for potency against canine and human neutral endopeptidase using target criteria of molecular weight <400 and log P between 2 and 4.5 to maximize the likelihood of achieving good oral absorption. The structure-activity relationship (SAR) investigations described in this paper led to the identification of an ethyl 1,3,4-thiadiazole glutaramide which demonstrated good neutral endopeptidase potency, selectivity and excellent oral absorption in the rat.
Department of Discovery Chemistry, Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK.
Graham N
GN
Maw
Alan
A
Stobie
Simon
S
Planken
David C
DC
Pryde
Vivienne
V
Sanderson
Michelle Y
MY
Platts
Martin
M
Corless
Peter
P
Stacey
Christopher
C
Wayman
Piet
P
Van Der Graaf
Christopher
C
Kohl
Sara
S
Coggon
Kevin
K
Beaumont
D000284:Administration, Oral; D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D003509:Cyclohexanecarboxylic Acids / Q000737:chemistry; D004285:Dogs; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008970:Molecular Weight; D015260:Neprilysin / Q000378:metabolism; D010421:Pentanoic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011480:Protease Inhibitors / Q000737:chemistry; D051381:Rats; D020018:Sexual Dysfunctions, Psychological / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
C511943:3-(1-((2-ethyl-1,3,4-thiazol-5-yl)aminocarbonyl)cyclopent-1-yl)-2-propylpropionic acid; D000577:Amides; D003509:Cyclohexanecarboxylic Acids; D004791:Enzyme Inhibitors; D010421:Pentanoic Acids; D011480:Protease Inhibitors; D013830:Thiadiazoles; C060942:candoxatrilat; D015260:Neprilysin