Discovery of potent and selective dipeptidyl peptidase IV inhibitors derived from beta-aminoamides bearing subsituted triazolopiperazines.
A series of beta-aminoamides bearing triazolopiperazines have been discovered as potent, selective, and orally active dipeptidyl peptidase IV (DPP-4) inhibitors by extensive structure-activity relationship (SAR) studies around the triazolopiperazine moiety. Among these, compound 34b with excellent in vitro potency (IC50 = 4.3 nM) against DPP-4, high selectivity over other enzymes, and good pharmacokinetic profiles exhibited pronounced in vivo efficacy in an oral glucose tolerance test (OGTT) in lean mice. On the basis of these properties, compound 34b has been profiled in detail. Further refinement of the triazolopiperazines resulted in the discovery of a series of extremely potent compounds with subnanomolar activity against DPP-4 (42b- 49b), that is, 4-fluorobenzyl-substituted compound 46b, which is notable for its superior potency (IC50 = 0.18 nM). X-ray crystal structure determination of compounds 34b and 46b in complex with DPP-4 enzyme revealed that (R)-stereochemistry at the 8-position of triazolopiperazines is strongly preferred over (S) with respect to DPP-4 inhibition.
Kim
Dooseop
D
Merck Research Laboratories, Merck & Company Inc, Rahway, NJ 07065, USA. dooseop_kim@merck.com
Kowalchick
Jennifer E
JE
Brockunier
Linda L
LL
Parmee
Emma R
ER
Eiermann
George J
GJ
Fisher
Michael H
MH
He
Huaibing
H
Leiting
Barbara
B
Lyons
Kathryn
K
Scapin
Giovanna
G
Patel
Sangita B
SB
Petrov
Aleksandr
A
Pryor
Kellyann D
KD
Roy
Ranabir Sinha
RS
Wu
Joseph K
JK
Zhang
Xiaoping
X
Wyvratt
Matthew J
MJ
Zhang
Bei B
BB
Zhu
Lan
L
Thornberry
Nancy A
NA
Weber
Ann E
AE
D000577:Amides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D018360:Crystallography, X-Ray; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004285:Dogs; D005951:Glucose Tolerance Test; D000882:Haplorhini; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011719:Pyrazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
C528501:4-(8-(4-fluorobenzyl)-3-(trifluoromethyl)-5,6-dihydro(1,2,4)triazolo(4,3-a)pyrazin-7(8H)-yl)-4-oxo-1-(2,4,5-trifluorophenyl)butan-2-amine; C528500:4-(8-methyl-3-(trifluoromethyl)-5,6-dihydro(1,2,4)triazolo(4,3-a)pyrazin-7(8H)-yl)-4-oxo-1-(2,4,5-trifluorophenyl)butan-2-amine; D000577:Amides; D054873:Dipeptidyl-Peptidase IV Inhibitors; D010879:Piperazines; D011719:Pyrazines; D014230:Triazoles; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4