Discovery of potent and selective orally bioavailable β-substituted phenylalanine derived dipeptidyl peptidase IV inhibitors

被引：46

作者：

Edmondson, SD

Mastracchio, A

Duffy, JL

Eiermann, GJ

He, HB

Ita, I

Leiting, B

Leone, JF

Lyons, KA

Makarewicz, AM

Patel, RA

Petrov, A

Wu, JK

Nancy, AT

Weber, AE

机构：

[1] Merck & Co Inc, Dept Med Chem, Rahway, NJ 07065 USA

[2] Merck & Co Inc, Dept Metab Disorders, Rahway, NJ 07065 USA

[3] Merck & Co Inc, Dept Pharmacol, Rahway, NJ 07065 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2005年 / 15卷 / 12期

关键词：

dipeptidyl peptidase IV; DPP-IV; DPPS; DPP9; QPP;

D O I：

10.1016/j.bmcl.2005.04.028

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

anti-Substituted biaryl beta-methylphenylalanine derived amides have been shown to be potent DPP-IV inhibitors that suffer from suboptimal selectivity and pharmacokinetics. This letter describes the substitution of the beta-methyl substituent with beta-polar substituents, culminating in the discovery of a beta-dimethylamide substituted phenylalanine derivative with an excellent potency, selectivity, and pharmacokinetic profile. (c) 2005 Elsevier Ltd. All rights reserved.

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收藏

页码：3048 / 3052

页数：5

相关论文

共 19 条

[1] Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes [J].

Ahrén, B ;

Landin-Olsson, M ;

Jansson, PA ;

Svensson, M ;

Holmes, D ;

Schweizer, A .

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2004, 89 (05) :2078-2084

[2] Fluoropyrrolidine amides as dipeptidyl peptidase IV inhibitors [J].

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 .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (05) :1265-1268

[3] A NEW SYSTEM FOR CATALYTIC ENANTIOSELECTIVE REDUCTION OF ACHIRAL KETONES TO CHIRAL ALCOHOLS - SYNTHESIS OF CHIRAL ALPHA-HYDROXY ACIDS [J].

COREY, EJ ;

BAKSHI, RK .

TETRAHEDRON LETTERS, 1990, 31 (05) :611-614

[4] NOVEL ELECTRONIC EFFECTS OF REMOTE SUBSTITUENTS ON THE OXAZABOROLIDINE-CATALYZED ENANTIOSELECTIVE REDUCTION OF KETONES [J].

COREY, EJ ;

HELAL, CJ .

TETRAHEDRON LETTERS, 1995, 36 (50) :9153-9156

[5] Therapeutic strategies based on glucagon-like peptide 1 [J].

Deacon, CF .

DIABETES, 2004, 53 (09) :2181-2189

[6] Inhibitors of dipeptidyl peptidase IV:: a novel approach for the prevention and treatment of Type 2 diabetes? [J].

Deacon, CF ;

Ahrén, B ;

Holst, JJ .

EXPERT OPINION ON INVESTIGATIONAL DRUGS, 2004, 13 (09) :1091-1102

[7] Glucagon-like peptide-1 receptor is involved in learning and neuroprotection [J].

During, MJ ;

Cao, L ;

Zuzga, DS ;

Francis, JS ;

Fitzsimons, HL ;

Jiao, XY ;

Bland, RJ ;

Klugmann, M ;

Banks, WA ;

Drucker, DJ ;

Haile, CN .

NATURE MEDICINE, 2003, 9 (09) :1173-1179

[8] Optimization of a tertiary alcohol series of phosphodiesterase-4 (PDE4) inhibitors:: Structure-activity relationship related to PDE4 inhibition and human ether-a-go-go related gene potassium channel binding affinity [J].

Friesen, RW ;

Ducharme, Y ;

Ball, RG ;

Blouin, M ;

Boulet, L ;

Côté, B ;

Frenette, R ;

Girard, M ;

Guay, D ;

Huang, Z ;

Jones, TR ;

Laliberté, F ;

Lynch, JJ ;

Mancini, J ;

Martins, E ;

Masson, P ;

Muise, E ;

Pon, DJ ;

Siegl, PKS ;

Styhler, A ;

Tsou, NN ;

Turner, MJ ;

Young, RN ;

Girard, Y .

JOURNAL OF MEDICINAL CHEMISTRY, 2003, 46 (12) :2413-2426

[9] Glucagon-like peptide 1 and inhibitors of dipeptidyl peptidase IV in the treatment of type 2 diabetes mellitus [J].

Holst, JJ ;

Deacon, CF .

CURRENT OPINION IN PHARMACOLOGY, 2004, 4 (06) :589-596

[10]

HOLST JJ, 2005, CURR OPIN ENDOCRINOL, V12, P56, DOI DOI 10.1055/S-2004-826158