Discovery of a potent and selective prostaglandin D2 receptor antagonist, [(3R)-4-(4-chloro-benzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]-acetic acid (MK-0524).
The discovery of the potent and selective prostaglandin D2 (PGD2) receptor (DP) antagonist [(3R)-4-(4-chlorobenzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]-acetic acid (13) is presented. Initial lead antagonists 6 and 7 were found to be potent and selective DP antagonists (DP Ki = 2.0 nM for each); however, they both suffered from poor pharmacokinetic profiles, short half-lives and high clearance rates in rats. Rat bile duct cannulation studies revealed that high concentrations of parent drug were present in the biliary fluid (Cmax = 1100 microM for 6 and 3900 microM for 7). This pharmacokinetic liability was circumvented by replacing the 7-methylsulfone substituent present in 6 and 7 with a fluorine atom resulting in antagonists with diminished propensity for biliary excretion and with superior pharmacokinetic profiles. Further optimization led to the discovery of the potent and selective DP antagonist 13.
Sturino
Claudio F
CF
Department of Medicinal Chemistry, Merck Frosst Canada & Co., 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada. claudio_sturino@merck.com
O'Neill
Gary
G
Lachance
Nicolas
N
Boyd
Michael
M
Berthelette
Carl
C
Labelle
Marc
M
Li
Lianhai
L
Roy
Bruno
B
Scheigetz
John
J
Tsou
Nancy
N
Aubin
Yves
Y
Bateman
Kevin P
KP
Chauret
Nathalie
N
Day
Stephen H
SH
Lévesque
Jean-François
JF
Seto
Carmai
C
Silva
Jose H
JH
Trimble
Laird A
LA
Carriere
Marie-Claude
MC
Denis
Danielle
D
Greig
Gillian
G
Kargman
Stacia
S
Lamontagne
Sonia
S
Mathieu
Marie-Claude
MC
Sawyer
Nicole
N
Slipetz
Deborah
D
Abraham
William M
WM
Jones
Tom
T
McAuliffe
Malia
M
Piechuta
Hana
H
Nicoll-Griffith
Deborah A
DA
Wang
Zhaoyin
Z
Zamboni
Robert
R
Young
Robert N
RN
Metters
Kathleen M
KM
D000402:Airway Obstruction / Q000188:drug therapy; D000818:Animals; D001646:Bile / Q000378:metabolism; D001667:Binding, Competitive; D004285:Dogs; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008861:Microsomes / Q000378:metabolism; D014663:Nasal Decongestants / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D012756:Sheep; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D007211:Indoles; C518174:MK-0524; D014663:Nasal Decongestants; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; C036293:prostaglandin D2 receptor