title: Novel heterocyclic DPP-4 inhibitors for the treatment of type 2 diabetes.
abstract: Novel deazaxanthine-based DPP-4 inhibitors have been identified that are potent (IC(50) <10nM) and highly selective versus other dipeptidyl peptidases. Their synthesis and SAR are reported, along with initial efforts to improve the PK profile through decoration of the deazaxanthine core. Optimisation of compound 3a resulted in the identification of compound (S)-4i, which displayed an improved in vitro and ADME profile. Further enhancements to the PK profile were possible by changing from the deazahypoxanthine to the deazaxanthine template, culminating in compound 12g, which displayed good ex vivo DPP-4 inhibition and a superior PK profile in rat, suggestive of once daily dosing in man.
authors.affiliation: Argenta Discovery 2009 Ltd, Harlow CM19 5TR, UK. jon.sutton@glpg.com
authors.forename: Jon M
authors.initials: JM
authors.lastname: Sutton
authors.forename: David E
authors.initials: DE
authors.lastname: Clark
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Dunsdon
authors.forename: Garry
authors.initials: G
authors.lastname: Fenton
authors.forename: Amanda
authors.initials: A
authors.lastname: Fillmore
authors.forename: Neil V
authors.initials: NV
authors.lastname: Harris
authors.forename: Chris
authors.initials: C
authors.lastname: Higgs
authors.forename: Chris A
authors.initials: CA
authors.lastname: Hurley
authors.forename: Sussie L
authors.initials: SL
authors.lastname: Krintel
authors.forename: Robert E
authors.initials: RE
authors.lastname: MacKenzie
authors.forename: Alokesh
authors.initials: A
authors.lastname: Duttaroy
authors.forename: Eric
authors.initials: E
authors.lastname: Gangl
authors.forename: Wiesia
authors.initials: W
authors.lastname: Maniara
authors.forename: Richard
authors.initials: R
authors.lastname: Sedrani
authors.forename: Kenji
authors.initials: K
authors.lastname: Namoto
authors.forename: Nils
authors.initials: N
authors.lastname: Ostermann
authors.forename: Bernd
authors.initials: B
authors.lastname: Gerhartz
authors.forename: Finton
authors.initials: F
authors.lastname: Sirockin
authors.forename: Jörg
authors.initials: J
authors.lastname: Trappe
authors.forename: Ulrich
authors.initials: U
authors.lastname: Hassiepen
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Baeschlin
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D018360:Crystallography, X-Ray; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D004789:Enzyme Activation / Q000187:drug effects; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D006571:Heterocyclic Compounds