(2R)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-α]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine:: A potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes

被引：718

作者：

Kim, D ^{[1
]}

Wang, LP ^{[1
]}

Beconi, M ^{[1
]}

Eiermann, GJ ^{[1
]}

Fisher, MH ^{[1
]}

He, HB ^{[1
]}

Hickey, GJ ^{[1
]}

Kowalchick, JE ^{[1
]}

Leiting, B ^{[1
]}

Lyons, K ^{[1
]}

Marsilio, F ^{[1
]}

McCann, ME ^{[1
]}

Patel, RA ^{[1
]}

Petrov, A ^{[1
]}

Scapin, G ^{[1
]}

Patel, SB ^{[1
]}

Roy, RS ^{[1
]}

Wu, JK ^{[1
]}

Wyvratt, MJ ^{[1
]}

Zhang, BB ^{[1
]}

Zhu, L ^{[1
]}

Thornberry, NA ^{[1
]}

Weber, AE ^{[1
]}

机构：

[1] Merck & Co Inc, Merck Res Labs, Rahway, NJ 07065 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2005年 / 48卷 / 01期

关键词：

D O I：

10.1021/jm0493156

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A novel series of beta-amino amides incorporating fused heterocycles, i.e., triazolopiperazines, were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV) for the treatment of type 2 diabetes. (2R)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (1) is a potent, orally active DPP-IV inhibitor (IC50 = 18 nM) with excellent selectivity over other proline-selective peptidases, oral bioavailability in preclinical species, and in vivo efficacy in animal models. MK-0431, the phosphate salt of compound 1, was selected for development as a potential new treatment for type 2 diabetes.

引用

页码：141 / 151

页数：11

共 53 条

[1] Cloning, expression and chromosomal localization of a novel human dipeptidyl peptidase (DPP) IV homolog, DPP8
Abbott, CA
Yu, DMT
Woollatt, E
Sutherland, GR
McCaughan, GW
Gorrell, MD
[J]. EUROPEAN JOURNAL OF BIOCHEMISTRY, 2000, 267 (20): : 6140 - 6150
[2] Diastereoselective synthesis and configuration-dependent activity of (3-substituted-cycloalkyl)glycine pyrrolidides and thiazolidides as dipeptidyl peptidase IV inhibitors
Ashton, WT
Dong, H
Sisco, RM
Doss, GA
Leiting, B
Patel, RA
Wu, JK
Marsilio, F
Thornberry, NA
Weber, AE
[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (04) : 859 - 863
[3] 4-cyanothiazolidides as very potent, stable inhibitors of dipeptidyl peptidase IV
Ashworth, DM
Atrash, B
Baker, GR
Baxter, AJ
Jenkins, PD
Jones, DM
Szelke, M
[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1996, 6 (22) : 2745 - 2748
[4] BRANNER KA, 2002, 28 NAT MED CHEM S AM
[5] Substituted piperazines as novel dipeptidyl peptidase IV inhibitors
Brockunier, LL
He, JF
Colwell, LF
Habulihaz, B
He, HB
Leiting, B
Lyons, KA
Marsilio, F
Patel, RA
Teffera, Y
Wu, JK
Thornberry, NA
Ann, AE
Parmee, ER
[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (18) : 4763 - 4766
[6] Brunger AT, 1998, ACTA CRYSTALLOGR D, V54, P905, DOI 10.1107/s0907444998003254
[7] Fluoropyrrolidine amides as dipeptidyl peptidase IV inhibitors
Caldwell, CG
Chen, P
He, JF
Parmee, ER
Leiting, B
Marsilio, F
Patel, RA
Wu, JK
Eiermann, GJ
Petrov, A
He, HB
Lyons, KA
Thornberry, NA
Weber, AE
[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (05) : 1265 - 1268
[8] 1-aminomethylisoquinoline-4-carboxylates as novel dipeptidylpeptidase IV inhibitors
Coppola, GM
Zhang, YL
Schuster, HF
Russell, ME
Hughes, TE
[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2000, 10 (14) : 1555 - 1558
[9] BOTH SUBCUTANEOUSLY AND INTRAVENOUSLY ADMINISTERED GLUCAGON-LIKE PEPTIDE-I ARE RAPIDLY DEGRADED FROM THE NH2-TERMINUS IN TYPE-II DIABETIC-PATIENTS AND IN HEALTHY-SUBJECTS
DEACON, CF
NAUCK, MA
TOFTNIELSEN, M
PRIDAL, L
WILLMS, B
HOLST, JJ
[J]. DIABETES, 1995, 44 (09) : 1126 - 1131
[10] Glucagon-like peptide-1: A basis for new approaches to the management of diabetes
Deacon, CF
Holst, JJ
Carr, RD
[J]. DRUGS OF TODAY, 1999, 35 (03) : 159 - 170

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