Design, synthesis, and SAR of potent and selective dipeptide-derived inhibitors for dipeptidyl peptidases.
In this paper we report the systematic search for new, potent, and selective DPP II inhibitors. A study of the structure-activity relationship was conducted starting from aminoacyl pyrrolidides as lead compounds. Rational exploration of the P(1) and P(2) building blocks led to the discovery of some very potent DPP II inhibitors which can be characterized by their high selectivity for DPP II with regard to DPP IV. Dab-Pip and Dab-Pip-2-CN were selected as the most promising inhibitors (IC(50) nM range) and will enable us to study the physiological role of DPP II and to differentiate between DPP II and DPP IV in biological systems.
Department of Medicinal Chemistry and Department of Medical Biochemistry, University of Antwerp (UIA), Universiteitsplein 1, B-2610 Antwerp, Belgium.
Kristel
K
Senten
Pieter
P
Van der Veken
Ingrid
I
De Meester
Anne-Marie
AM
Lambeir
Simon
S
Scharpé
Achiel
A
Haemers
Koen
K
Augustyns
D000596:Amino Acids / Q000138:chemical synthesis* / Q000737:chemistry; D001386:Azides / Q000138:chemical synthesis / Q000737:chemistry; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015195:Drug Design; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship
D000596:Amino Acids; D001386:Azides; D004151:Dipeptides; D009570:Nitriles; D010880:Piperidines; D011759:Pyrrolidines; D015842:Serine Proteinase Inhibitors; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C100151:dipeptidyl peptidase II; D018819:Dipeptidyl Peptidase 4