title: Identification and optimization of anthranilic sulfonamides as novel, selective cholecystokinin-2 receptor antagonists.
abstract: A high throughput screening approach to the identification of selective cholecystokinin-2 receptor (CCK-2R) ligands resulted in the discovery of a novel series of antagonists, represented by 1-[2-[(2,1,3-benzothiadiazol-4-ylsulfonyl)amino]-5-chlorobenzoyl]-piperidine (1; CCK-2R, pK(I) = 6.4). Preliminary exploration of the structure-activity relationships around the anthranilic ring and the amide and sulfonamide moieties led to a nearly 50-fold improvement of receptor affinity and showed a greater than 1000-fold selectivity over the related cholecystokinin-1 receptor. Pharmacokinetic evaluation led to the identification of 4-[4-iodo-2-[(5-quinoxalinylsulfonyl)amino]benzoyl]-morpholine, 26d, a compound that demonstrates promising pharmacokinetic properties in the rat and dog with respect to plasma clearance and oral bioavailability and is a potent inhibitor in vivo of pentagastrin-stimulated acid secretion in the rat when dosed orally.
authors.affiliation: Johnson and Johnson Pharmaceutical Research and Development, LLC, 3210 Merryfield Row, San Diego, California 92121, USA.
authors.forename: Brett D
authors.initials: BD
authors.lastname: Allison
authors.forename: Victor K
authors.initials: VK
authors.lastname: Phuong
authors.forename: Laura C
authors.initials: LC
authors.lastname: McAtee
authors.forename: Mark
authors.initials: M
authors.lastname: Rosen
authors.forename: Magda
authors.initials: M
authors.lastname: Morton
authors.forename: Clodagh
authors.initials: C
authors.lastname: Prendergast
authors.forename: Terry
authors.initials: T
authors.lastname: Barrett
authors.forename: Guy
authors.initials: G
authors.lastname: Lagaud
authors.forename: Jamie
authors.initials: J
authors.lastname: Freedman
authors.forename: Lina
authors.initials: L
authors.lastname: Li
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wu
authors.forename: Hariharan
authors.initials: H
authors.lastname: Venkatesan
authors.forename: Marna
authors.initials: M
authors.lastname: Pippel
authors.forename: Craig
authors.initials: C
authors.lastname: Woods
authors.forename: Michèle C
authors.initials: MC
authors.lastname: Rizzolio
authors.forename: Michael
authors.initials: M
authors.lastname: Hack
authors.forename: Kenway
authors.initials: K
authors.lastname: Hoey
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Deng
authors.forename: Christopher
authors.initials: C
authors.lastname: King
authors.forename: Nigel P
authors.initials: NP
authors.lastname: Shankley
authors.forename: Michael H
authors.initials: MH
authors.lastname: Rabinowitz
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001682:Biological Availability; D004285:Dogs; D004355:Drug Stability; D005704:Gallbladder / Q000187:drug effects / Q000502:physiology; D005744:Gastric Acid / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009025:Morpholines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D043886:Receptor, Cholecystokinin A / Q000037:antagonists & inhibitors; D043887:Receptor, Cholecystokinin B / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013270:Stomach / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D062367:ortho-Aminobenzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C515138:4-(4-iodo-2-((5-quinoxalinylsulfonyl)amino)benzoyl)morpholine; D009025:Morpholines; D011810:Quinoxalines; D043886:Receptor, Cholecystokinin A; D043887:Receptor, Cholecystokinin B; D013449:Sulfonamides; D062367:ortho-Aminobenzoates