共查询到20条相似文献,搜索用时 15 毫秒
1.
Schroeder GM Chen XT Williams DK Nirschl DS Cai ZW Wei D Tokarski JS An Y Sack J Chen Z Huynh T Vaccaro W Poss M Wautlet B Gullo-Brown J Kellar K Manne V Hunt JT Wong TW Lombardo LJ Fargnoli J Borzilleri RM 《Bioorganic & medicinal chemistry letters》2008,18(6):1945-1951
An amide library derived from the pyrrolo[2,1-f][1,2,4]triazine scaffold led to the identification of modest inhibitors of Met kinase activity. Introduction of polar side chains at C-6 of the pyrrolotriazine core provided significant improvements in in vitro potency. The amide moiety could be replaced with acylurea and malonamide substituents to give compounds with improved potency in the Met-driven GTL-16 human gastric carcinoma cell line. Acylurea pyrrolotriazines with substitution at C-5 demonstrated single digit nanomolar kinase activity. X-ray crystallography revealed that the C-5 substituted pyrrolotriazines bind to the Met kinase domain in an ATP-competitive manner. 相似文献
2.
Zych AJ Lam SQ Jenkins DM Herr RJ Ting PC Lee JF Kuang R Wu H Kim DW Aslanian RG Wainhaus S Black TA Cacciapuoti A McNicholas PM Xu Y Walker SS 《Bioorganic & medicinal chemistry letters》2012,22(14):4896-4899
The structure-activity relationship studies of a novel sulfonylurea series of piperazine pyridazine-based small molecule glucan synthase inhibitors is described. The optimization of PK profiles within the series led to the discovery of several compounds with improved pharmacokinetic profiles which demonstrated in vitro potency against clinically relevant strains. However, the advancement of compounds from this series into a non-lethal systemic fungal infection model failed to show in vivo efficacy. 相似文献
3.
Zheng X Hodgetts KJ Brielmann H Hutchison A Burkamp F Brian Jones A Blurton P Clarkson R Chandrasekhar J Bakthavatchalam R De Lombaert S Crandall M Cortright D Blum CA 《Bioorganic & medicinal chemistry letters》2006,16(19):5217-5221
Bioisosteric replacement of piperazine with an aryl ring in lead VR1 antagonist 1 led to the biarylamide series. The development of B-ring SAR led to the conformationally constrained analog 70. The resulting aminoquinazoline 70 represents a novel VR1 antagonist with improved in vitro potency and oral bioavailability vs the analogous compounds from the lead series. 相似文献
4.
Birch AM Kenny PW Oikonomakos NG Otterbein L Schofield P Whittamore PR Whalley DP 《Bioorganic & medicinal chemistry letters》2007,17(2):394-399
A series of substituted 3,4-dihydro-2-quinolone glycogen phosphorylase inhibitors, which have potential as antidiabetic agents, is described. Initial members of the series showed good enzyme inhibitory potency but poor physical properties. Optimisation of the 1-substituent led to 2,3-dihydroxypropyl compounds which showed good in vitro potency and improved physical properties, together with good DMPK profiles and acute in vivo efficacy in a rat model. X-ray crystallographic data are presented, showing an unexpected variety of binding orientations at the dimer interface site. 相似文献
5.
P D Williams M G Bock B E Evans R M Freidinger S N Gallicchio M T Guidotti M A Jacobson M S Kuo M R Levy E V Lis S R Michelson J M Pawluczyk D S Perlow D J Pettibone A G Quigley D R Reiss C Salvatore K J Stauffer C J Woyden 《Bioorganic & medicinal chemistry letters》1999,9(9):1311-1316
Structure-activity studies on the oxytocin antagonist 1 (L-371,257; Ki = 9.3 nM) have led to the identification of a related series of compounds containing an ortho-trifluoroethoxyphenylacetyl core which are orally bioavailable and have significantly improved potency in vitro and in vivo, e.g., compound 8 (L-374,943; Ki = 1.4 nM). 相似文献
6.
《Bioorganic & medicinal chemistry letters》2014,24(1):152-155
We have previously reported a series of 2,4,6-trisubstituted pyrimidines as potent A2A receptor antagonists. The leading compounds often feature a potentially labile acetamide functional group which tends to hydrolyze under acidic conditions. Here we report the replacement of the acetamide functional group with bioisosteres. This effort led us to a new series of adenosine A2A receptor antagonists with improved potency and chemical stability. 相似文献
7.
Feng DM Wai JM Kuduk SD Ng C Murphy KL Ransom RW Reiss D Chang RS Harrell CM MacNeil T Tang C Prueksaritanont T Freidinger RM Pettibone DJ Bock MG 《Bioorganic & medicinal chemistry letters》2005,15(9):2385-2388
A novel class of 2,3-diaminopyridine bradykinin B1 receptor antagonists is disclosed. Structure-activity relationship studies (SARs) that led to compounds with significantly improved potency and pharmacokinetic properties relative to the lead compound are described. 相似文献
8.
Li AR Johnson MG Liu J Chen X Du X Mihalic JT Deignan J Gustin DJ Duquette J Fu Z Zhu L Marcus AP Bergeron P McGee LR Danao J Lemon B Carabeo T Sullivan T Ma J Tang L Tonn G Collins TL Medina JC 《Bioorganic & medicinal chemistry letters》2008,18(2):688-693
A series of six-six and six-five fused heterocyclic CXCR3 antagonists has been synthesized and their activities evaluated in an [(125)I]-IP-10 displacement assay and an ITAC mediated in vitro cell migration assay. The pharmacokinetic properties of several top compounds have also been studied. This effort led to the discovery of compounds with increased potency and improved pharmacokinetic properties that could serve as useful tools to study the role of the CXCR3 receptor in vivo. 相似文献
9.
John J. Parlow Mary W. Burney Brenda L. Case Thomas J. Girard Kerri A. Hall Peter K. Harris Ronald R. Hiebsch Rita M. Huff Rhonda M. Lachance Deborah A. Mischke Stephen R. Rapp Rhonda S. Woerndle Michael D. Ennis 《Bioorganic & medicinal chemistry letters》2010,20(4):1388-1394
Efforts to refine the SAR of the piperazinyl-glutamate-pyridines for more potent analogs with improved pharmacokinetic profiles are described. Exploring substituted piperidines and other ring systems at the 4-pyridyl position led to compounds with improved potency and pharmacokinetic properties over candidate I. In particular, compounds 4t and 5t were discovered with a 10-fold improvement over potency and improved pharmacokinetic profiles in both the rat and dog. 相似文献
10.
N-aryl-piperidine-4-carboxamides as a novel class of potent inhibitors of MALT1 proteolytic activity
Achim Schlapbach Laszlo Revesz Carole Pissot Soldermann Thomas Zoller Catherine H. Régnier Frédéric Bornancin Thomas Radimerski Jutta Blank Ansgar Schuffenhauer Martin Renatus Paulus Erbel Samu Melkko Richard Heng Oliver Simic Ralf Endres Markus Wartmann Jean Quancard 《Bioorganic & medicinal chemistry letters》2018,28(12):2153-2158
Starting from a weak screening hit, potent and selective inhibitors of the MALT1 protease function were elaborated. Advanced compounds displayed high potency in biochemical and cellular assays. Compounds showed activity in a mechanistic Jurkat T cell activation assay as well as in the B-cell lymphoma line OCI-Ly3, which suggests potential use of MALT1 inhibitors in the treatment of autoimmune diseases as well as B-cell lymphomas with a dysregulated NF-κB pathway. Initially, rat pharmacokinetic properties of this compound series were dominated by very high clearance which could be linked to amide cleavage. Using a rat hepatocyte assay a good in vitro-in vivo correlation could be established which led to the identification of compounds with improved PK properties. 相似文献
11.
Design, synthesis, and evaluation of a new class of noncyclic 1,3-dicarbonyl compounds as PPARalpha selective activators 总被引:2,自引:0,他引:2
Li Z Liao C Ko BC Shan S Tong EH Yin Z Pan D Wong VK Shi L Ning ZQ Hu W Zhou J Chung SS Lu XP 《Bioorganic & medicinal chemistry letters》2004,14(13):3507-3511
Lipid accumulation in nonadipose tissues is increasingly linked to the development of type 2 diabetes in obese individuals. We report here the design, synthesis, and evaluation of a series of novel PPARalpha selective activators containing 1,3-dicarbonyl moieties. Structure-activity relationship studies led to the identification of PPARalpha selective activators (compounds 10, 14, 17, 18, and 21) with stronger potency and efficacy to activate PPARalpha over PPARgamma and PPARdelta. Experiments in vivo showed that compounds 10, 14, and 17 had blood glucose lowering effect in diabetic db/db mouse model after two weeks oral dosing. The data strongly support further testing of these lead compounds in other relevant disease animal models to evaluate their potential therapeutic benefits. 相似文献
12.
Many human tumours exhibit activation of the PI3K (phosphoinositide 3-kinase)/Akt pathway, and inhibition of this pathway slows tumour growth. This led to the development of specific Akt inhibitors for in vivo use. However, activation of Akt is also necessary for processes including glucose metabolism. Therefore a potential complication of such anticancer drugs is insulin resistance and/or diabetes. In the process of characterizing the metabolic effects of early-phase Akt inhibitors, we discovered an off-target inhibitory effect on mammalian facilitative glucose transporters. In view of the crucial role of glucose transport for all mammalian cells, such an off-target effect would have major implications for further development of this family of compounds. In the present study, we have characterized a next-generation Akt inhibitor, MK-2206. MK-2206 is an orally active allosteric Akt inhibitor under development for treating solid tumours. We report that MK-2206 potently inhibits Thr308Akt and Ser473Akt phosphorylation in 3T3-L1 adipocytes (IC50 0.11 and 0.18 μM respectively) as well as downstream effects of insulin on GLUT4 (glucose transporter 4) translocation (IC50 0.47 μM) and glucose transport (IC50 0.14 μM). Notably, the potency of MK-2206 is approximately 1 log higher than previous inhibitors and its specificity is significantly improved with modest inhibitory effects on glucose transport in GLUT4-expressing adipocytes and GLUT1-rich human erythrocytes, independently of Akt. Nevertheless, MK-2206 clearly has potent effects on Akt2, the principal isoform involved in peripheral insulin action, in which case insulin resistance will probably be a major complication following in vivo administration. We conclude that MK-2206 provides an optimal tool for studying the effects of Akt in vitro. 相似文献
13.
Michael T. Rudd John A. McCauley Joseph J. Romano John W. Butcher Kimberly Bush Charles J. McIntyre Kevin T. Nguyen Kevin F. Gilbert Terry A. Lyle M. Katharine Holloway Bang-Lin Wan Joseph P. Vacca Vincenzo Summa Steven Harper Michael Rowley Steven S. Carroll Christine Burlein Jillian M. DiMuzio Adam Gates Donald J. Graham Nigel J. Liverton 《Bioorganic & medicinal chemistry letters》2012,22(23):7201-7206
A series of macrocyclic compounds containing 2-substituted-quinoline moieties have been discovered and shown to exhibit excellent HCV NS3/4a genotype 3a and genotype 1b R155K mutant activity while maintaining the high rat liver exposure. Cyclization of the 2-substituted quinoline substituent led to a series of tricyclic P2 compounds which also display superb gt3a potency. 相似文献
14.
Nagarajan SR De Crescenzo GA Getman DP Lu HF Sikorski JA Walker JL McDonald JJ Houseman KA Kocan GP Kishore N Mehta PP Funkes-Shippy CL Blystone L 《Bioorganic & medicinal chemistry》2003,11(22):4769-4777
The human immunodeficiency virus (HIV) has been shown to be the causative agent for AIDS. The HIV virus encodes for a unique aspartyl protease that is essential for the production of enzymes and proteins in the final stages of maturation. Protease inhibitors have been useful in combating the disease. The inhibitors incorporate a variety of isosteres including the hydroxyethylurea at the protease cleavage site. We have shown that the replacement of t-butylurea moiety by benzothiazolesulfonamide provided inhibitors with improved potency and antiviral activities. Some of the compounds have shown good oral bioavailability and half-life in rats. The synthesis of benzothiazole derivatives led us to explore other heterocycles. During the course of our studies, we also developed an efficient synthesis of benzothiazole-6-sulfonic acid via a two-step procedure starting from sulfanilamide. 相似文献
15.
Dymock B Barril X Beswick M Collier A Davies N Drysdale M Fink A Fromont C Hubbard RE Massey A Surgenor A Wright L 《Bioorganic & medicinal chemistry letters》2004,14(2):325-328
Multiple co-crystal structures of an adenine-based series of inhibitors bound to the molecular chaperone Hsp90 have been determined. These structures explain the observed SAR for previously described compounds and new compounds, which possess up to 8-fold improved potency against the isolated enzyme. Anti-tumour cell potency and mechanism of action data is also described for the most potent compounds. These data should enable the design of more potent Hsp90 inhibitors. 相似文献
16.
McGowan D Vendeville S Lin TI Tahri A Hu L Cummings MD Amssoms K Berke JM Canard M Cleiren E Dehertogh P Last S Fransen E Van Der Helm E Van den Steen I Vijgen L Rouan MC Fanning G Nyanguile O Van Emelen K Simmen K Raboisson P 《Bioorganic & medicinal chemistry letters》2012,22(13):4431-4436
Novel conformationaly constrained 1,6- and 2,6-macrocyclic HCV NS5b polymerase inhibitors, in which either the nitrogen or the phenyl ring in the C2 position of the central indole core is tethered to an acylsulfamide acid bioisostere, have been designed and tested for their anti-HCV potency. This transformational route toward non-zwitterionic finger loop-directed inhibitors led to the discovery of derivatives with improved cell potency and pharmacokinetic profile. 相似文献
17.
David J. Richard Jeroen C. Verheijen Kevin Curran Joshua Kaplan Lourdes Toral-Barza Irwin Hollander Judy Lucas Ker Yu Arie Zask 《Bioorganic & medicinal chemistry letters》2009,19(24):6830-6835
A series of highly potent and selective pyrazolopyrimidine mTOR inhibitors which contain water-solubilizing groups attached to the 6-arylureidophenyl moiety have been prepared. Such derivatives displayed superior potency to those in which these appendages were attached to alternative sites. In comparison to unfunctionalized arylureido compounds, these analogs demonstrated enhanced cellular potency and significantly improved stability towards human microsomes, resulting in an mTOR inhibitor with impressive efficacy in a xenograft model with an intermittent dosing regimen. 相似文献
18.
Takehiko Iwaki Yuji Nakamura Taisaku Tanaka Yasuyuki Ogawa Osamu Iwamoto Yoshihiko Okamura Yumi Kawase Mayumi Furuya Yoshiaki Oyama Takahiro Nagayama 《Bioorganic & medicinal chemistry letters》2017,27(21):4904-4907
Novel thienopyrimidine compounds 2 and 3 were discovered from high-throughput screening as Natriuretic Peptide Receptor A (NPR-A) agonists. Scaffold hopping of a thienopyrimidine ring to a quinazoline ring, introduction of the basic functional group and optimization of the substituent on the 6-position of the benzene ring of quinazoline led to improved agonistic activity. We discovered compound 48, which showed potent agonistic activity for NPR-A with an EC50 value of 0.073 μM, indicating 350-fold potency compared to the hit compound 3. 相似文献
19.
Cushing TD Adrian J Chen X DiMaio H Doughan B Flygare J Liang L Mayorga V Miao S Mellon H Peterson MG Powers JP Spector F Stein C Wright M Xu D Ye Q Jaen J 《Bioorganic & medicinal chemistry letters》2006,16(18):4879-4883
Infection by human cytomegalovirus (hCMV) remains a potent threat to susceptible people throughout the world. We have discovered a series of imidazolyl-pyrimidine compounds, which were found to be irreversible inhibitors of the hCMV UL70 primase based on results from radiolabeling and SAR studies. Two promising analogs are described that rival ganciclovir and cidofovir in antiviral potency and possess improved cytotoxicity profiles. 相似文献
20.
Marsilje TH Alper PB Lu W Mutnick D Michellys PY He Y Karanewsky DS Chow D Gerken A Lao J Kim MJ Seidel HM Tian SS 《Bioorganic & medicinal chemistry letters》2008,18(19):5259-5262
The lead optimization of a novel series of benzo[a]carbazole-based small molecule agonists of the thrombopoietin (Tpo) receptor is reported. The chemical instability of the dihydro-benzo[a]carbazole lead 2 was successfully addressed in the design and evaluation of compounds which also demonstrated improved potency compared to 2. Members of the scaffold have been identified which are full agonists that demonstrate cellular functional potency <50 nM. Analog 21 demonstrates equivalent efficacy in the human megakaryocyte differentiation (CFU-mega) assay compared to Eltrombopag. 相似文献