title: Tetrapeptide CCK agonists: structure-activity studies on modifications at the N-terminus.
abstract: We had reported earlier on a novel series of potent and selective tetrapeptide cholecystokinin-A (CCK-A) agonists of the general structure Boc-Trp-Lys[epsilon-Y]-Asp-N(R)PheNH2 [Y = amides, ureas; R = H, Me] that were potent anorectic agents in rats. In an effort to optimize the potency, selectivity, stability, and efficacy of our lead candidate A-71623 [R = Me, Y = o-tolylaminocarbonyl; Tac] toward development of a clinical candidate, we have explored a series of analogues in which the N-terminal Boc functionality was systematically replaced with various amides, ureas, carbamates, and sulfonamides of differing size, hydrophobicity, and stereoelectronic properties. In general, these analogues maintained good potency and selectivity for the CCK-A receptor (guinea pig pancreas), as well as potent anorectic activity in rats. Those analogues exhibiting equal or superior activity compared to A-71623 but differing physicochemical properties may represent superior drug candidates.
authors.affiliation: Department 47W, Abbott Laboratories, Abbott Park, Illinois 60064.
authors.forename: R L
authors.initials: RL
authors.lastname: Elliott
authors.forename: H
authors.initials: H
authors.lastname: Kopecka
authors.forename: M J
authors.initials: MJ
authors.lastname: Bennett
authors.forename: Y K
authors.initials: YK
authors.lastname: Shue
authors.forename: R
authors.initials: R
authors.lastname: Craig
authors.forename: C W
authors.initials: CW
authors.lastname: Lin
authors.forename: B R
authors.initials: BR
authors.lastname: Bianchi
authors.forename: T R
authors.initials: TR
authors.lastname: Miller
authors.forename: D G
authors.initials: DG
authors.lastname: Witte
authors.forename: M A
authors.initials: MA
authors.lastname: Stashko
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001067:Appetite Depressants / Q000737:chemistry / Q000494:pharmacology*; D002766:Cholecystokinin; D006168:Guinea Pigs; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013758:Tetragastrin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology
chemical_list: D001067:Appetite Depressants; D009842:Oligopeptides; D013758:Tetragastrin; C066278:A 71623; D002766:Cholecystokinin