title: Discovery of potent and selective dipeptidyl peptidase IV inhibitors derived from beta-aminoamides bearing subsituted triazolopiperazines.
abstract: 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.
authors.affiliation: Merck Research Laboratories, Merck & Company Inc, Rahway, NJ 07065, USA. dooseop_kim@merck.com
authors.forename: Dooseop
authors.initials: D
authors.lastname: Kim
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Kowalchick
authors.forename: Linda L
authors.initials: LL
authors.lastname: Brockunier
authors.forename: Emma R
authors.initials: ER
authors.lastname: Parmee
authors.forename: George J
authors.initials: GJ
authors.lastname: Eiermann
authors.forename: Michael H
authors.initials: MH
authors.lastname: Fisher
authors.forename: Huaibing
authors.initials: H
authors.lastname: He
authors.forename: Barbara
authors.initials: B
authors.lastname: Leiting
authors.forename: Kathryn
authors.initials: K
authors.lastname: Lyons
authors.forename: Giovanna
authors.initials: G
authors.lastname: Scapin
authors.forename: Sangita B
authors.initials: SB
authors.lastname: Patel
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Petrov
authors.forename: Kellyann D
authors.initials: KD
authors.lastname: Pryor
authors.forename: Ranabir Sinha
authors.initials: RS
authors.lastname: Roy
authors.forename: Joseph K
authors.initials: JK
authors.lastname: Wu
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhang
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Wyvratt
authors.forename: Bei B
authors.initials: BB
authors.lastname: Zhang
authors.forename: Lan
authors.initials: L
authors.lastname: Zhu
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Thornberry
authors.forename: Ann E
authors.initials: AE
authors.lastname: Weber
mesh_terms: 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
chemical_list: 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