Abstract
The successful launches of dipeptidyl peptidase IV (DPP IV) inhibitors as oral anti-diabetics warrant and spur the further quest for additional chemical entities in this promising class of therapeutics. Numerous pharmaceutical companies have pursued their proprietary candidates towards the clinic, resulting in a large body of published chemical structures associated with DPP IV. Herein, we report the discovery of a novel chemotype for DPP IV inhibition based on the C-(1-aryl-cyclohexyl)-methylamine scaffold and its optimization to compounds which selectively inhibit DPP IV at low-nM potency and exhibit an excellent oral pharmacokinetic profile in the rat.
Keywords:
Dipeptidyl peptidase IV; Enzyme selectivity; Ex vivo plasma DPP IV inhibition; Pharmacokinetics; Protease inhibition; Structure-based drug design.
Copyright © 2014 Elsevier Ltd. All rights reserved.
MeSH terms
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Adamantane / analogs & derivatives
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Adamantane / chemistry
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Adamantane / pharmacology
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Administration, Oral
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Animals
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Caco-2 Cells
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Crystallography, X-Ray
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Cyclization
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Dipeptidyl Peptidase 4 / metabolism*
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Dipeptidyl-Peptidase IV Inhibitors / chemical synthesis*
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Dipeptidyl-Peptidase IV Inhibitors / chemistry
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Dipeptidyl-Peptidase IV Inhibitors / pharmacokinetics*
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Dipeptidyl-Peptidase IV Inhibitors / pharmacology
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Drug Discovery*
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Enzyme Activation / drug effects
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Humans
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Inhibitory Concentration 50
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Methylamines / chemical synthesis*
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Methylamines / chemistry
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Methylamines / pharmacokinetics*
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Methylamines / pharmacology
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Molecular Structure
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Nitriles / chemistry
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Nitriles / pharmacology
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Pyrazines / chemistry
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Pyrazines / pharmacology
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Pyrrolidines / chemistry
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Pyrrolidines / pharmacology
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Rats
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Sitagliptin Phosphate
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Triazoles / chemistry
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Triazoles / pharmacology
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Vildagliptin
Substances
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Dipeptidyl-Peptidase IV Inhibitors
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Methylamines
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Nitriles
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Pyrazines
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Pyrrolidines
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Triazoles
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DPP4 protein, human
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Dipeptidyl Peptidase 4
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Vildagliptin
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Adamantane
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Sitagliptin Phosphate