title: Design, synthesis, and tripeptidyl peptidase II inhibitory activity of a novel series of (S)-2,3-dihydro-2-(4-alkyl-1H-imidazol-2-yl)-1H-indoles.
abstract: Butabindide, 1, was previously reported as a potent inhibitor (IC50 = 7 nM) of the serine protease enzyme tripeptidyl peptidase II (TPPII), an endogenous protease that degrades cholecystokinin-8 (CCK-8). We found that 1 has some inherent chemical instability, yielding diketopiperazine 2 fairly readily under mimicked physiological conditions. We therefore prepared imidazoles 3, which are void of 1's inherent instability, and have found that our novel analogues maintained comparable TPPII inhibitory activity (e.g.,for 3c, IC50 = 4 nM) as 1.
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Welsh and McKean Roads, P.O. Box 776, Spring House, Pennsylvania 19477-0776, USA. HBreslin@prdus.jnj.com
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Breslin
authors.forename: Tamara A
authors.initials: TA
authors.lastname: Miskowski
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kukla
authors.forename: William H
authors.initials: WH
authors.lastname: Leister
authors.forename: Hans L
authors.initials: HL
authors.lastname: De Winter
authors.forename: Diane A
authors.initials: DA
authors.lastname: Gauthier
authors.forename: Maria V F
authors.initials: MV
authors.lastname: Somers
authors.forename: Daniëlle C G
authors.initials: DC
authors.lastname: Peeters
authors.forename: Peter W M
authors.initials: PW
authors.lastname: Roevens
mesh_terms: D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D012697:Serine Endopeptidases / Q000737:chemistry*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D007211:Indoles; D015842:Serine Proteinase Inhibitors; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C048001:tripeptidyl-peptidase 2; D012697:Serine Endopeptidases