共查询到20条相似文献,搜索用时 15 毫秒
1.
Caldwell CG Chen P He J Parmee ER Leiting B Marsilio F Patel RA Wu JK Eiermann GJ Petrov A He H Lyons KA Thornberry NA Weber AE 《Bioorganic & medicinal chemistry letters》2004,14(5):1265-1268
Amides derived from fluorinated pyrrolidines and 4-substituted cyclohexylglycine analogues have been prepared and evaluated as inhibitors of dipeptidyl dipeptidase IV (DP-IV). Analogues which incorporated (S)-3-fluoropyrrolidine showed good selectivity for DP-IV over quiescent cell proline dipeptidase (QPP). Compound 48 had good pharmacokinetic properties and was orally active in an oral glucose tolerance test in lean mice. 相似文献
2.
Kurukulasuriya R Rohde JJ Szczepankiewicz BG Basha F Lai C Jae HS Winn M Stewart KD Longenecker KL Lubben TW Ballaron SJ Sham HL von Geldern TW 《Bioorganic & medicinal chemistry letters》2006,16(24):6226-6230
A series of xanthine mimetics containing 5,5 and 5,6 heterocycle fused imidazoles were synthesized as dipeptidyl peptidase IV inhibitors. Compound 7 is potent (h-DPPIV Ki = 2 nM) and exhibits excellent selectivity and no species specificity against rat and human enzymes. The X-ray structure confirms that the binding mode of 7 to rat DPPIV is similar to the parent xanthines. 相似文献
3.
Brockunier LL He J Colwell LF Habulihaz B He H Leiting B Lyons KA Marsilio F Patel RA Teffera Y Wu JK Thornberry NA Weber AE Parmee ER 《Bioorganic & medicinal chemistry letters》2004,14(18):4763-4766
Incorporation of a fluorophenyl beta-amino amide moiety into piperazine screening lead 2 has resulted in the discovery of a structurally novel series of potent and selective DP-IV inhibitors. Simplification of the molecule and incorporation of multiple fluorine atoms on the phenyl ring has provided low molecular weight analogs such as compound 32, which is a 19nM DP-IV inhibitor with >4000-fold selectivity over QPP. 相似文献
4.
Zhao G Taunk PC Magnin DR Simpkins LM Robl JA Wang A Robertson JG Marcinkeviciene J Sitkoff DF Parker RA Kirby MS Hamann LG 《Bioorganic & medicinal chemistry letters》2005,15(18):3992-3995
Dipeptidyl peptidase IV (DPP4) is a multifunctional type II transmembrane serine peptidase which regulates various physiological processes, most notably plasma glucose homeostasis by cleaving peptide hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. Inhibition of DPP4 is a potentially valuable therapy for type 2 diabetes. Synthesis and structure-activity relationships of a series of substituted diprolyl nitriles are described, leading to the identification of compound 1 with a measured DPP4 K(i) of 3.6 nM. 相似文献
5.
Betty Lam Zhiyuan Zhang Jeffery A. Stafford Robert J. Skene Lihong Shi Stephen L. Gwaltney 《Bioorganic & medicinal chemistry letters》2012,22(21):6628-6631
Dipeptidyl peptidase IV (DPP-4) inhibitors have been shown to enhance GLP-1 levels and thereby improve hyperglycemia in type II diabetes. From a small fragment hit, using structure-based design, we have discovered a new class of non-covalent, potent and selective DPP-4 inhibitors. 相似文献
6.
Parmee ER He J Mastracchio A Edmondson SD Colwell L Eiermann G Feeney WP Habulihaz B He H Kilburn R Leiting B Lyons K Marsilio F Patel RA Petrov A Di Salvo J Wu JK Thornberry NA Weber AE 《Bioorganic & medicinal chemistry letters》2004,14(1):43-46
Substituted 4-amino cyclohexylglycine analogues were evaluated for DP-IV inhibitory properties. Bis-sulfonamide 15e was an extremely potent 2.6 nM inhibitor of the enzyme with excellent selectivity over all counterscreens. 2,4-difluorobenzenesulfonamide 15b and 1-naphthyl amide 16b, however, combined an acceptable in vitro profile with good pharmacokinetic properties in the rat, and 15b was orally efficacious at 3 mpk in an OGTT in lean mice. 相似文献
7.
Edmondson SD Wei L Xu J Shang J Xu S Pang J Chaudhary A Dean DC He H Leiting B Lyons KA Patel RA Patel SB Scapin G Wu JK Beconi MG Thornberry NA Weber AE 《Bioorganic & medicinal chemistry letters》2008,18(7):2409-2413
The synthesis, selectivity, rat pharmacokinetic profile, and drug metabolism profiles of a series of potent fluoroolefin-derived DPP-4 inhibitors (4) are reported. A radiolabeled fluoroolefin 33 was shown to possess a high propensity to form reactive metabolites, thus revealing a potential liability for this class of DPP-4 inhibitors. 相似文献
8.
Simpkins LM Bolton S Pi Z Sutton JC Kwon C Zhao G Magnin DR Augeri DJ Gungor T Rotella DP Sun Z Liu Y Slusarchyk WS Marcinkeviciene J Robertson JG Wang A Robl JA Atwal KS Zahler RL Parker RA Kirby MS Hamann LG 《Bioorganic & medicinal chemistry letters》2007,17(23):6476-6480
The synthesis and structure-activity relationships of novel dipeptidyl peptidase IV inhibitors replacing the classical cyanopyrrolidine P1 group with other small nitrogen heterocycles are described. A unique potency enhancement was achieved with beta-branched natural and unnatural amino acids, particularly adamantylglycines, linked to a (2S,3R)-2,3-methanopyrrolidine based scaffold. 相似文献
9.
Ferraris D Ko YS Calvin D Chiou T Lautar S Thomas B Wozniak K Rojas C Kalish V Belyakov S 《Bioorganic & medicinal chemistry letters》2004,14(22):5579-5583
In this paper, the synthesis and structure-activity relationships (SAR) of two classes of electrophile-based dipeptidyl peptidase IV (DPP IV) inhibitors, the ketopyrrolidines and ketoazetidines, is discussed. The SAR of these series demonstrate that the 2-thiazole, 2-benzothiazole, and 2-pyridylketones are optimal S1' binding groups for potency against DPP IV. In addition, both cyclohexyl glycine (CHG) and octahydroindole carboxylate (OIC) serve as the most potent S2 binding groups within each series. Stereochemistry at the alpha-position of the central ring is relevant to potency within the ketopyrrolidines series, but not in the ketoazetidine series. Finally, the ketoazetidines display enhanced stability over the corresponding ketopyrrolidines, while maintaining their potency. In fact, certain stabilized ketoazetidines can maintain their in vitro potency and inhibit DPP IV in the plasma for up to 6h. 相似文献
10.
Lu IL Lee SJ Tsu H Wu SY Kao KH Chien CH Chang YY Chen YS Cheng JH Chang CN Chen TW Chang SP Chen X Jiaang WT 《Bioorganic & medicinal chemistry letters》2005,15(13):3271-3275
To find potent and selective inhibitors of dipeptidyl peptidase IV (DPP-IV), we synthesized a series of 2-cyanopyrrolidine with P2-site 4-substituted glutamic acid derivatives and tested their activities against DPP-IV, DPP8, and DPP-II. Analogues that incorporated a bulky substituent at the first carbon position of benzylamine or isoquinoline showed over 30-fold selectivity for DPP-IV over both DPP8 and DPP-II. From structure-activity relationship studies, we speculate that the S2 site of DPP8 might be similar to that of DPP-IV, while DPP-IV inhibitor with N-substituted glycine in the P2 site and/or with a moiety involving in hydrophobic interaction with the side chain of Phe357 might provide a better selectivity for DPP-IV over DPP8. 相似文献
11.
Hulin B Cabral S Lopaze MG Van Volkenburg MA Andrews KM Parker JC 《Bioorganic & medicinal chemistry letters》2005,15(21):4770-4773
Cyclohexylglycine amides of various fluorinated pyrrolidines and azetidines were prepared and tested for activity against dipeptidyl peptidase IV and in vivo in the KK mouse model of type 2 diabetes. The tetrafluoropyrrolidide, cis-3,4-difluoropyrrolidide and the fluorinated azetidides displayed unexpectedly strong activity. 相似文献
12.
The sole application of an inhibitor of the dipeptidyl peptidase DP IV (also DP 4, CD26, DPP-IV or DPP-4) to a mammal subsequently leading to improved glucose tolerance marks a major breakthrough in metabolic research bearing the potential of a new revolutionary diabetes therapy. This was demonstrated in rat applying the specific DP IV inhibitor isoleucyl thiazolidine. It was published in 1996 for the first time that a specific DP IV inhibitor in a given dose was able to completely block glucagon-like peptide-1 (GLP-1) degradation in vivo resulting in improved insulin response accompanied, by accelerated peripheral glucose disposal. Later on, these results were confirmed by several research teams applying DP IV inhibitors intravenously or orally. Today, the DP IV inhibition for the treatment of metabolic disorders is a validated principle. Now, more than 10 years after the initial animal experiments, first DP IV inhibitors as investigational drugs are tested in phase 3 clinical trials. 相似文献
13.
Wallace MB Feng J Zhang Z Skene RJ Shi L Caster CL Kassel DB Xu R Gwaltney SL 《Bioorganic & medicinal chemistry letters》2008,18(7):2362-2367
A novel series of non-covalent, benzimidazole-based inhibitors of DPP-4 has been developed from a small fragment hit using structure-based drug design. A highly versatile synthetic route was created for the development of SAR, which led to the discovery of potent and selective inhibitors with excellent pharmaceutical properties. 相似文献
14.
Edmondson SD Mastracchio A Beconi M Colwell LF Habulihaz B He H Kumar S Leiting B Lyons KA Mao A Marsilio F Patel RA Wu JK Zhu L Thornberry NA Weber AE Parmee ER 《Bioorganic & medicinal chemistry letters》2004,14(20):5151-5155
In-house screening of the Merck sample collection identified proline derived homophenylalanine 3 as a DPP-IV inhibitor with modest potency (DPP-IV IC50=1.9 microM). Optimization of 3 led to compound 37, which is among the most potent and selective DPP-IV inhibitors discovered to date. 相似文献
15.
Lübbers T Böhringer M Gobbi L Hennig M Hunziker D Kuhn B Löffler B Mattei P Narquizian R Peters JU Ruff Y Wessel HP Wyss P 《Bioorganic & medicinal chemistry letters》2007,17(11):2966-2970
In a search for novel DPP-IV inhibitors, 2-aminobenzo[a]quinolizines were identified as submicromolar HTS hits. Due to the difficult synthetic access to this compound class, 1,3-disubstituted 4-aminopiperidines were used as model compounds for optimization. The developed synthetic methodology and the SAR could be transferred to the 2-aminobenzo[a]quinolizine series, leading to highly active DPP-IV inhibitors. 相似文献
16.
Tsai TY Coumar MS Hsu T Hsieh HP Chien CH Chen CT Chang CN Lo YK Wu SH Huang CY Huang YW Wang MH Wu HY Lee HJ Chen X Chao YS Jiaang WT 《Bioorganic & medicinal chemistry letters》2006,16(12):3268-3272
A series of substituted pyrrolidine-2,4-dicarboxylic acid amides were synthesized as potential antidiabetic agents, and many of them showed good in vitro DPP-IV inhibition (IC50 = 2-250 nM) with selectivity over DPP-II, DPP8, and FAP enzymes. Selected compounds 8c and 11a showed in vivo plasma DPP-IV inhibition after oral administration in Wistar rats. 相似文献
17.
Chen P Caldwell CG Mathvink RJ Leiting B Marsilio F Patel RA Wu JK He H Lyons KA Thornberry NA Weber AE 《Bioorganic & medicinal chemistry letters》2007,17(21):5853-5857
A series of substituted imidazopiperidine amides has been prepared and evaluated for inhibition of dipeptidyl peptidase IV (DPP-4). Substitution at the 1- and 3-positions produced increased selectivity for DPP-4 relative to DPP-8 and DPP-9. Compounds in this series had IC(50) values as low as 5.8 nM for inhibition of DPP-4. 相似文献
18.
Ting-Yueh Tsai Tsu Hsu Chiung-Tong Chen Jai-Hong Cheng Teng-Kuang Yeh Xin Chen Chung-Yu Huang Chung-Nien Chang Kai-Chia Yeh Su-Huei Hsieh Chia-Hui Chien Yi-Wei Chang Chih-Hsiang Huang Yu-Wen Huang Chen-Lung Huang Ssu-Hui Wu Min-Hsien Wang Cheng-Tai Lu Yu-Sheng Chao Weir-Torn Jiaang 《Bioorganic & medicinal chemistry》2009,17(6):2388-2399
A series of trans-2-aryl-cyclopropylamine derived compounds were synthesized and evaluated their biological activities against DPP-IV. The structure-activity relationships (SAR) led to the discovery of novel series of DPP-IV inhibitors, having IC50 values of <100 nM with excellent selectivity over the closely related enzymes, DPP8, DPP-II and FAP. The studies identified a potent and selective DPP-IV inhibitor 24b, which exhibited the ability to both significantly inhibit plasma DPP-IV activity in rats and improve glucose tolerance in lean mice and diet induced obese mice. 相似文献
19.
McIntosh CH Demuth HU Kim SJ Pospisilik JA Pederson RA 《The international journal of biochemistry & cell biology》2006,38(5-6):860-872
A number of alternative therapies for type 2 diabetes are currently under development that take advantage of the actions of the incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide on the pancreatic beta-cell. One such approach is based on the inhibition of dipeptidyl peptidase IV (DP IV), the major enzyme responsible for degrading the incretins in vivo. DP IV exhibits characteristics that have allowed the development of specific inhibitors with proven efficacy in improving glucose tolerance in animal models of diabetes and type 2 human diabetics. While enhancement of insulin secretion, resulting from blockade of incretin degradation, has been proposed to be the major mode of inhibitor action, there is also evidence that inhibition of gastric emptying, reduction in glucagon secretion and important effects on beta-cell differentiation, mitogenesis and survival, by the incretins and other DP IV-sensitive peptides, can potentially preserve beta-cell mass, and improve insulin secretory function and glucose handling in diabetics. 相似文献
20.
Kondo T Sugimoto I Nekado T Ochi K Ohtani T Tajima Y Yamamoto S Kawabata K Nakai H Toda M 《Bioorganic & medicinal chemistry》2007,15(7):2715-2735
A series of (4-substituted prolyl)prolinenitriles were synthesized and evaluated as inhibitors of dipeptidylpeptidase IV (DPP-IV). Among those tested, the 4beta-[4-(hydroxyphenyl)prolyl]prolinenitriles showed a potent inhibitory activity with a long duration of action. Metabolic formation of the corresponding phenol glucuronates was found to contribute to their long duration of action. The activity profiles of the synthesized compounds are reported and structure-activity relationships are also presented. 相似文献