The discovery of novel 5,6,5- and 5,5,6-tricyclic pyrrolidines as potent and selective DPP-4 inhibitors

[Display omitted] Novel potent and selective 5,6,5- and 5,5,6-tricyclic pyrrolidine dipeptidyl peptidase IV (DPP-4) inhibitors were identified. Structure–activity relationship (SAR) efforts focused on improving the intrinsic DPP-4 inhibition potency, increasing protease selectivity, and demonstratin...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2016-06, Vol.26 (11), p.2622-2626
Main Authors: Cox, Jason M., Chu, Hong D., Kuethe, Jeffrey T., Gao, Ying-Duo, Scapin, Giovanna, Eiermann, George, He, Huaibing, Li, Xiaohua, Lyons, Kathryn A., Metzger, Joseph, Petrov, Aleksandr, Wu, Joseph K., Xu, Shiyao, Sinha-Roy, Ranabir, Weber, Ann E., Biftu, Tesfaye
Format: Article
Language:English
Subjects:
Animals
Crystallography, X-Ray
Dipeptidyl Peptidase 4 - metabolism
Dipeptidyl peptidase IV (DPP-4)
Dipeptidyl-Peptidase IV Inhibitors - chemical synthesis
Dipeptidyl-Peptidase IV Inhibitors - chemistry
Dipeptidyl-Peptidase IV Inhibitors - pharmacology
Dogs
Dose-Response Relationship, Drug
Drug Discovery
Humans
Models, Molecular
Molecular Structure
Omarigliptin
Pyrrolidines - chemical synthesis
Pyrrolidines - chemistry
Pyrrolidines - pharmacology
Rats
Sitagliptin
Structure-Activity Relationship
Type 2 diabetes mellitus
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Summary:[Display omitted] Novel potent and selective 5,6,5- and 5,5,6-tricyclic pyrrolidine dipeptidyl peptidase IV (DPP-4) inhibitors were identified. Structure–activity relationship (SAR) efforts focused on improving the intrinsic DPP-4 inhibition potency, increasing protease selectivity, and demonstrating clean ion channel and cytochrome P450 profiles while trying to achieve a pharmacokinetic profile suitable for once weekly dosing in humans.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2016.04.020