Fluoro-Olefins as Peptidomimetic Inhibitors of Dipeptidyl Peptidases

Abstract

The feasibility of the fluoro-olefin function as a peptidomimetic group in inhibitors for dipeptidyl peptidase IV and II (DPP IV and DPP II) is investigated by evaluation of N-substituted Gly-Psi[CF=C]pyrrolidines, Gly-Psi[CF=C]piperidines, and Gly-Psi[CF=C](2-cyano)pyrrolidines. Of this later class, the (Z)- and (E)-fluoro-olefin analogues were prepared and chemical stability in comparison with the parent amide was checked. Most of these compounds exhibited a strong binding preference toward DPP II with IC(50) values in the low micromolar range, while only low DPP IV inhibitory potential is seen.

11 Years of Cyanopyrrolidines as DPP-IV Inhibitors

“…The decreased activities were explained by the inability of the fluoroolefins to form strong hydrogen bonds to DPP-IV's Asn710 and Arg125 (compare Fig. (3)) [143]. With similar compounds, it was found that the omittance of the nitrile does not lead to a reduction in activity [143].…”

“…(3)) [143]. With similar compounds, it was found that the omittance of the nitrile does not lead to a reduction in activity [143]. This might suggest that these compounds have a different binding mode, with no covalent interaction with Ser630.…”

The fluoroalkene motif as a surrogate of the amide bond: syntheses of AA-Ψ[(Z) and (E)-CFCH]-Pro pseudodipeptides and an Enalapril analogue

“…1) was constructed by Welch et al via a Peterson fluoroolefination reaction. 6 Augustyns et al generated the fluoroolefin moiety by a HornereWadswortheEmmons reaction, 7 as also reported by Chang et al in the synthesis of the dipeptide Val-J[(Z)-CF]CH]-Pro for the design of an efficient hepatitis C virus NS5A inhibitor. 8 Our group reported the synthesis of the dipeptide Ala-J [CF]CH]-Pro with enhanced E:Z ratio as well as excellent diastereoselectivity.…”

Prolyl Peptidases Related to Dipeptidyl Peptidase IV: Potential of Specific Inhibitors in Drug Discovery.

“…However, the electrophile is also responsible for the instability inherent in these compounds due to reaction with the free amino group of the P 2 amino acid. It has been demonstrated that the amino group intramolecularly cyclizes to the nitrile forming a six-membered cyclic amidine, followed by hydrolysis to the diketopiperazine [71,72].…”

“…Further optimization of the P 2 position by alkylation of the γ-amino function yielded subnanomolar DPP II inhibitors with extremely high selectivity over DPP IV and DPP8 (28, UAMC00039) [92]. Selective DPP II inhibition over DPP IV was also observed in N-alkylglycylpiperidines (29) and their fluoro-olefin analogues (30) [72]. In a series of diphenyl phosphonate dipeptide analogues compound 31 was the most potent and selective DPP II inhibitor [93].…”