title: Aryl- and heteroaryl-substituted aminobenzo[a]quinolizines as dipeptidyl peptidase IV inhibitors.
abstract: Synthesis and SAR are described for a structurally distinct class of DPP-IV inhibitors based on aminobenzo[a]quinolizines bearing (hetero-)aromatic substituents in the S1 specificity pocket. The m-(fluoromethyl)-phenyl derivative (S,S,S)-2g possesses the best fit in the S1 pocket. However, (S,S,S)-2i, bearing a more hydrophilic 5-methyl-pyridin-2-yl residue as substituent for the S1 pocket, displays excellent in vivo activity and superior drug-like properties.
authors.affiliation: F Hoffmann-La Roche Ltd, Pharma Research, CH-4070 Basel, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Boehringer
authors.forename: Holger
authors.initials: H
authors.lastname: Fischer
authors.forename: Michael
authors.initials: M
authors.lastname: Hennig
authors.forename: Daniel
authors.initials: D
authors.lastname: Hunziker
authors.forename: Joerg
authors.initials: J
authors.lastname: Huwyler
authors.forename: Bernd
authors.initials: B
authors.lastname: Kuhn
authors.forename: Bernd M
authors.initials: BM
authors.lastname: Loeffler
authors.forename: Thomas
authors.initials: T
authors.lastname: Luebbers
authors.forename: Patrizio
authors.initials: P
authors.lastname: Mattei
authors.forename: Robert
authors.initials: R
authors.lastname: Narquizian
authors.forename: Elena
authors.initials: E
authors.lastname: Sebokova
authors.forename: Urs
authors.initials: U
authors.lastname: Sprecher
authors.forename: Hans Peter
authors.initials: HP
authors.lastname: Wessel
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D011480:Protease Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011807:Quinolizines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011924:Rats, Zucker
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D011480:Protease Inhibitors; D011807:Quinolizines; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4