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Discovery of C-(1-aryl-cyclohexyl)-methylamines as selective, orally available inhibitors of dipeptidyl peptidase IV.

Namoto, Kenji and Sirockin, Finton and Ostermann, Nils and Gessier, Francois and Flohr, Stefanie and Sedrani, Richard and Gerhartz, Bernd and Trappe, Joerg and Hassiepen, Ulrich and Duttaroy, Alokesh and Ferreira, Suzie and Sutton, Jon M. and Clark, David E. and Fenton, Gary and Beswick, Mandy and Baeschlin, Daniel (2014) Discovery of C-(1-aryl-cyclohexyl)-methylamines as selective, orally available inhibitors of dipeptidyl peptidase IV. Bioorganic & Medicinal Chemistry Letters, 24 (3). pp. 731-736.

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 DPPIV 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 phamacokinetic profile in the rat.

Item Type: Article
Keywords: protease inhibition, dipeptidyl peptidase IV, structure-based drug design, selectivity, pharmacokinetics
Date Deposited: 04 May 2016 23:45
Last Modified: 04 May 2016 23:45
URI: https://oak.novartis.com/id/eprint/10024

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