4-arylcyclohexylalanine analogs as potent, selective, and orally active inhibitors of dipeptidyl peptidase IV

David E Kaelin; Abigail L Smenton; George J Eiermann; Huaibing He; Barbara Leiting; Kathryn A Lyons; Reshma A Patel; Sangita B Patel; Alexsandr Petrov; Giovanna Scapin; Joseph K Wu; Nancy A Thornberry; Ann E Weber; Joseph L Duffy

doi:10.1016/j.bmcl.2007.08.049

4-arylcyclohexylalanine analogs as potent, selective, and orally active inhibitors of dipeptidyl peptidase IV

Bioorg Med Chem Lett. 2007 Nov 1;17(21):5806-11. doi: 10.1016/j.bmcl.2007.08.049. Epub 2007 Aug 26.

Authors

David E Kaelin¹, Abigail L Smenton, George J Eiermann, Huaibing He, Barbara Leiting, Kathryn A Lyons, Reshma A Patel, Sangita B Patel, Alexsandr Petrov, Giovanna Scapin, Joseph K Wu, Nancy A Thornberry, Ann E Weber, Joseph L Duffy

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. [email protected]

PMID: 17851076
DOI: 10.1016/j.bmcl.2007.08.049

Abstract

A novel series of 4-arylcyclohexylalanine DPP-4 inhibitors was synthesized and tested for inhibitory activity as well as selectivity over the related proline-specific enzymes DPP-8 and DPP-9. Optimization of this series led to 28 (DPP-4 IC(50)=4.8 nM), which showed an excellent pharmacokinetic profile across several preclinical species. Evaluation of 28 in an oral glucose tolerance test demonstrated that this compound effectively reduced glucose excursion in lean mice.

MeSH terms

Administration, Oral
Alanine / analogs & derivatives*
Alanine / chemistry
Alanine / pharmacology
Animals
Area Under Curve
Dipeptidyl-Peptidase IV Inhibitors*
Mice
Models, Molecular
Protease Inhibitors / administration & dosage
Protease Inhibitors / chemistry
Protease Inhibitors / pharmacokinetics
Protease Inhibitors / pharmacology*

Substances

Dipeptidyl-Peptidase IV Inhibitors
Protease Inhibitors
Alanine