Synthesis and characterization of constrained peptidomimetic dipeptidyl peptidase IV inhibitors: amino-lactam boroalanines.
We describe here the epimerization-free synthesis and characterization of a new class of conformationally constrained lactam aminoboronic acid inhibitors of dipeptidyl peptidase IV (DPP IV; E.C. 3.4.14.5). These compounds have the advantage that they cannot undergo the pH-dependent cyclization prevalent in most dipeptidyl boronic acids that attenuates their potency at physiological pH. For example, D-3-amino-1-[L-1-boronic-ethyl]-pyrrolidine-2-one (amino-D-lactam-L-boroAla), one of the best lactam inhibitors of DPP IV, is several orders of magnitude less potent than L-Ala-L-boroPro, as measured by Ki values (2.3 nM vs 30 pM, respectively). At physiological pH, however, it is actually more potent than L-Ala-L-boroPro, as measured by IC50 values (4.2 nM vs 1400 nM), owing to the absence of the potency-attenuating cyclization. In an interesting and at first sight surprising reversal of the relationship between stereochemistry and potency observed with the conformationally unrestrained Xaa-boroPro class of inhibitors, the L-L diastereomers of the lactams are orders of magnitude less effective than the D-L lactams. However, this interesting reversal and the unexpected potency of the D-L lactams as DPP IV inhibitors can be understood in structural terms, which is explained and discussed here.
Lai
Jack H
JH
Contribution from the Department of Biochemistry, Tufts University School of Medicine, 136 Harrison Avenue, Boston, Massachusetts 02111, USA.
Wu
Wengen
W
Zhou
Yuhong
Y
Maw
Hlaing H
HH
Liu
Yuxin
Y
Milo
Lawrence J
LJ
Poplawski
Sarah E
SE
Henry
Gillian D
GD
Sudmeier
James L
JL
Sanford
David G
DG
Bachovchin
William W
WW
D000409:Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D032701:Biomimetics; D001888:Boric Acids / Q000138:chemical synthesis* / Q000737:chemistry; D001897:Boronic Acids / Q000138:chemical synthesis* / Q000737:chemistry; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry*; D054873:Dipeptidyl-Peptidase IV Inhibitors; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007769:Lactams / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry*; D011760:Pyrrolidinones / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C520857:3-amino-1-(1-boronic-ethyl)pyrrolidine-2-one; D001888:Boric Acids; D001897:Boronic Acids; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007769:Lactams; D010455:Peptides; D011760:Pyrrolidinones; D018819:Dipeptidyl Peptidase 4; D000409:Alanine