共查询到20条相似文献,搜索用时 15 毫秒
1.
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
2.
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
3.
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
4.
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
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.
Juan M. Betancort David T. Winn Ruzhang Liu Quansheng Xu Junjuan Liu Wensheng Liao Shu-Hui Chen David Carney Denise Hanway James Schmeits Xinqiang Li Eric Gordon David A. Campbell 《Bioorganic & medicinal chemistry letters》2009,19(15):4437-4440
The synthesis and biochemical evaluation of novel cyanothiazolidine inhibitors of dipeptidyl peptidase 4 (DPP4) is described. Their main structural feature is a constrained bicyclic core that prevents the intramolecular formation of inactive cyclic species. The inhibitors show good to moderate biochemical potency against DPP4 and display distinct selectivity profiles towards DPP7, DPP8 and DPP9 depending on their substitution. 相似文献
7.
Guohua Zhao Chet Kwon Aiying Wang James G. Robertson Jovita Marcinkeviciene Rex A. Parker Mark S. Kirby Lawrence G. Hamann 《Bioorganic & medicinal chemistry letters》2013,23(6):1622-1625
Synthesis and structure–activity relationship of a series of substituted piperidinyl glycine 2-cyano-4,5-methano pyrroline DPP-IV inhibitors are described. Improvement of the inhibitory activity and chemical stability of this series of compounds was respectively achieved by the introduction of bulky groups at the 4-position and 1-position of the piperidinyl glycine, leading to a series of potent and stable DPP-IV inhibitors. 相似文献
8.
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
9.
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
10.
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
11.
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
12.
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
13.
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
14.
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
15.
Abe M Akiyama T Umezawa Y Yamamoto K Nagai M Yamazaki H Ichikawa Y Muraoka Y 《Bioorganic & medicinal chemistry》2005,13(3):785-797
The structure of sulphostin (1), a novel dipeptidyl peptidase IV (DPP-IV) inhibitor, is consisted of three key functional groups, including a characteristic amino(sulfoamino)phosphinyl group, on a piperidine ring. To examine the relationship between its structure and the inhibitory activity against DPP-IV, various analogues were synthesized and their activities were investigated. These results indicated that all of the functional groups on the piperidine ring were crucial to the DPP-IV inhibitory activity of sulphostin, and that the sulfonic acid group, which constructed the amino(sulfoamino)phosphinyl group, contributed to the stability of the compound. Moreover, those functional groups should be adjoined on the piperidine ring for the inhibitory activity. The size of the nitrogen-containing heterocyclic ring including piperidine appeared to scarcely affect the activity. In the present study, the sulfonic acid-deficient five-membered ring analogue 27a showed the strongest inhibitory activity (IC50=11 nM). 相似文献
16.
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
17.
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
18.
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
19.
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
20.
Qiao L Baumann CA Crysler CS Ninan NS Abad MC Spurlino JC Desjarlais RL Kervinen J Neeper MP Bayoumy SS Williams R Deckman IC Dasgupta M Reed RL Huebert ND Tomczuk BE Moriarty KJ 《Bioorganic & medicinal chemistry letters》2006,16(1):123-128
The discovery, SAR, and X-ray crystal structure of novel biarylaminoacyl-(S)-2-cyano-pyrrolidines and biarylaminoacylthiazolidines as potent inhibitors of dipeptidyl peptidase IV (DPP IV) are reported. 相似文献