title: 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).
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Merck Frosst Canada & Co., 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada. claudio_sturino@merck.com
authors.forename: Claudio F
authors.initials: CF
authors.lastname: Sturino
authors.forename: Gary
authors.initials: G
authors.lastname: O'Neill
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lachance
authors.forename: Michael
authors.initials: M
authors.lastname: Boyd
authors.forename: Carl
authors.initials: C
authors.lastname: Berthelette
authors.forename: Marc
authors.initials: M
authors.lastname: Labelle
authors.forename: Lianhai
authors.initials: L
authors.lastname: Li
authors.forename: Bruno
authors.initials: B
authors.lastname: Roy
authors.forename: John
authors.initials: J
authors.lastname: Scheigetz
authors.forename: Nancy
authors.initials: N
authors.lastname: Tsou
authors.forename: Yves
authors.initials: Y
authors.lastname: Aubin
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Bateman
authors.forename: Nathalie
authors.initials: N
authors.lastname: Chauret
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Day
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Lévesque
authors.forename: Carmai
authors.initials: C
authors.lastname: Seto
authors.forename: Jose H
authors.initials: JH
authors.lastname: Silva
authors.forename: Laird A
authors.initials: LA
authors.lastname: Trimble
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Carriere
authors.forename: Danielle
authors.initials: D
authors.lastname: Denis
authors.forename: Gillian
authors.initials: G
authors.lastname: Greig
authors.forename: Stacia
authors.initials: S
authors.lastname: Kargman
authors.forename: Sonia
authors.initials: S
authors.lastname: Lamontagne
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Mathieu
authors.forename: Nicole
authors.initials: N
authors.lastname: Sawyer
authors.forename: Deborah
authors.initials: D
authors.lastname: Slipetz
authors.forename: William M
authors.initials: WM
authors.lastname: Abraham
authors.forename: Tom
authors.initials: T
authors.lastname: Jones
authors.forename: Malia
authors.initials: M
authors.lastname: McAuliffe
authors.forename: Hana
authors.initials: H
authors.lastname: Piechuta
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nicoll-Griffith
authors.forename: Zhaoyin
authors.initials: Z
authors.lastname: Wang
authors.forename: Robert
authors.initials: R
authors.lastname: Zamboni
authors.forename: Robert N
authors.initials: RN
authors.lastname: Young
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Metters
mesh_terms: 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
chemical_list: D007211:Indoles; C518174:MK-0524; D014663:Nasal Decongestants; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; C036293:prostaglandin D2 receptor