Aryl- and heteroaryl-substituted aminobenzo[a]quinolizines as dipeptidyl peptidase IV inhibitors.
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.
Boehringer
Markus
M
F Hoffmann-La Roche Ltd, Pharma Research, CH-4070 Basel, Switzerland.
Fischer
Holger
H
Hennig
Michael
M
Hunziker
Daniel
D
Huwyler
Joerg
J
Kuhn
Bernd
B
Loeffler
Bernd M
BM
Luebbers
Thomas
T
Mattei
Patrizio
P
Narquizian
Robert
R
Sebokova
Elena
E
Sprecher
Urs
U
Wessel
Hans Peter
HP
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
D054873:Dipeptidyl-Peptidase IV Inhibitors; D011480:Protease Inhibitors; D011807:Quinolizines; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4