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.
Maw
Graham N
GN
Department of Discovery Chemistry, Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK.
Stobie
Alan
A
Planken
Simon
S
Pryde
David C
DC
Sanderson
Vivienne
V
Platts
Michelle Y
MY
Corless
Martin
M
Stacey
Peter
P
Wayman
Christopher
C
Van Der Graaf
Piet
P
Kohl
Christopher
C
Coggon
Sara
S
Beaumont
Kevin
K
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