title: Gamma-amino-substituted analogues of 1-[(S)-2,4-diaminobutanoyl]piperidine as highly potent and selective dipeptidyl peptidase II inhibitors.
abstract: Using 1-[(S)-2,4-diaminobutanoyl]piperidine as lead compound, we developed a large series of highly potent and selective dipeptidyl peptidase II (DPP II) inhibitors. gamma-Amino substitution with arylalkyl groups, for example, a 2-chlorobenzyl moiety, resulted in a DPP II inhibitor with an IC(50) = 0.23 nM and a high selectivity toward DPP IV (IC(50) = 345 microM). Furthermore, it was shown that the basicity of the gamma-amino is important and that alpha-amino substitution is not favorable. Piperidine-2-nitriles did not show an increase in potency but rather reduced the selectivity. Introduction of a 4-methyl or a 3-fluorine on piperidine improved selectivity and preserved the high potency.
authors.affiliation: Department of Medicinal Chemistry, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium.
authors.forename: Kristel
authors.initials: K
authors.lastname: Senten
authors.forename: Pieter
authors.initials: P
authors.lastname: Van Der Veken
authors.forename: Ingrid
authors.initials: I
authors.lastname: De Meester
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Lambeir
authors.forename: Simon
authors.initials: S
authors.lastname: Scharpé
authors.forename: Achiel
authors.initials: A
authors.lastname: Haemers
authors.forename: Koen
authors.initials: K
authors.lastname: Augustyns
mesh_terms: D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D010880:Piperidines; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C100151:dipeptidyl peptidase II; D018819:Dipeptidyl Peptidase 4