Design, Synthesis, and Evaluation of a Series of Novel Super Long-Acting DPP‑4 Inhibitors for the Treatment of Type 2 Diabetes

In
the present work, a novel series of trifluoromethyl-substituted
tetrahydropyran derivatives were rationally designed and synthesized
as potent DPP-4 inhibitors with significantly improved duration time
of action over current commercially available DPP-4 inhibitors. The
incorporation of the trifluoromethyl group on the 6-position of the
tetrahydropyran ring of omarigliptin with the configuration of (2R,3S,5R,6S) not only significantly improves the overall pharmacokinetic profiles
in mice but also maintains comparable DPP-4 inhibition activities.
Further preclinical development of compound 2 exhibited
its extraordinary efficacy in vivo and good safety
profile. Clinical studies of compound 2 (Haisco HSK7653)
are now ongoing in China, which revealed that inhibitor 2 could serve as an efficient candidate with a once-biweekly therapeutic
regimen.