共查询到20条相似文献,搜索用时 0 毫秒
1.
Nuria Aguilar Marta Mir Pedro M. Grima Manel López Victor Segarra Laia Esteban Imma Moreno Nuria Godessart Gema Tarrasón Teresa Domenech Dolors Vilella Clara Armengol Mònica Córdoba Mar Sabaté Daniel Casals Maria Domínguez 《Bioorganic & medicinal chemistry letters》2012,22(24):7672-7676
Amido-1,3,4-thiadiazoles have been identified as a novel structural class of potent and selective sphingosine-1-phosphate receptor subtype 1 agonists. Starting from a micromolar HTS hit with the help of an in-house homology model, robust structural–activity relationships were developed to yield compounds with good selectivity and excellent in vivo efficacy in rat models. 相似文献
2.
Meng Q Zhao B Xu Q Xu X Deng G Li C Luan L Ren F Wang H Xu H Xu Y Zhang H Xiang JN Elliott JD Guo TB Zhao Y Zhang W Lu H Lin X 《Bioorganic & medicinal chemistry letters》2012,22(8):2794-2797
Novel indole-propionic acid derivatives were developed as sphingosine-1-phosphate (S1P) receptor agonists through a systematic SAR study. The optimized and S1P(3) selective S1P(1) agonist 9f induced peripheral blood lymphocyte reduction in vivo and has an excellent efficacy in mouse experimental autoimmune encephalomyelitis (EAE). 相似文献
3.
Miguel Guerrero Ramulu Poddutoori Mariangela Urbano Xuemei Peng Timothy P. Spicer Peter S. Chase Peter S. Hodder Marie-Therese Schaeffer Steven Brown Hugh Rosen Edward Roberts 《Bioorganic & medicinal chemistry letters》2013,23(23):6346-6349
Potent and selective S1P3 receptor (S1P3-R) agonists may represent important proof-of-principle tools used to clarify the receptor biological function and assess the therapeutic potential of the S1P3-R in cardiovascular, inflammatory and pulmonary diseases. N,N-Dicyclohexyl-5-propylisoxazole-3-carboxamide was identified by a high-throughput screening of MLSMR library as a promising S1P3-R agonist. Rational chemical modifications of the hit allowed the identification of N,N-dicyclohexyl-5-cyclopropylisoxazole-3-carboxamide, a S1P3-R agonist endowed with submicromolar activity and exquisite selectivity over the remaining S1P1,2,4,5-R family members. A combination of ligand competition, site-directed mutagenesis and molecular modeling studies showed that the N,N-dicyclohexyl-5-cyclopropylisoxazole-3-carboxamide is an allosteric agonist and binds to the S1P3-R in a manner that does not disrupt the S1P3-R–S1P binding. The lead molecule herein disclosed constitutes a valuable pharmacological tool to explore the molecular basis of the receptor function, and provides the bases for further rational design of more potent and drug-like S1P3-R allosteric agonists. 相似文献
4.
Xia Y Chackalamannil S Greenlee WJ Jayne C Neustadt B Stamford A Vaccaro H Xu XL Baker H O'Neill K Woods M Hawes B Kowalski T 《Bioorganic & medicinal chemistry letters》2011,21(11):3290-3296
The lead optimization studies of a series of GPR119 agonists incorporating a nortropanol scaffold are described. Extensive structure-activity relationship (SAR) studies of the lead compound 20f led to the identification of compound 36j as a potent, single digit nanomolar GPR119 agonist with high agonist activity. Compound 36j was orally active in lowering blood glucose levels in a mouse oral glucose tolerance test and increased plasma insulin levels in a rat hyperglycemic model. It showed good to excellent pharmacokinetic properties in rats and monkeys and no untoward activities in counter-screen assays. Compound 36j demonstrated an attractive in vitro and in vivo profile for further development. 相似文献
5.
Kim RM Chang J Lins AR Brady E Candelore MR Dallas-Yang Q Ding V Dragovic J Iliff S Jiang G Mock S Qureshi S Saperstein R Szalkowski D Tamvakopoulos C Tota L Wright M Yang X Tata JR Chapman K Zhang BB Parmee ER 《Bioorganic & medicinal chemistry letters》2008,18(13):3701-3705
The discovery and optimization of potent and selective aminobenzimidazole glucagon receptor antagonists are described. One compound possessing moderate pharmacokinetic properties in multiple preclinical species was orally efficacious at inhibiting glucagon-mediated glucose excursion in transgenic mice expressing the human glucagon receptor, and in rhesus monkeys. The compound also significantly lowered glucose levels in a murine model of diabetes. 相似文献
6.
Tomoharu Tsukada Osamu Kanno Takahiro Yamane Jun Tanaka Taishi Yoshida Akira Okuno Takeshi Shiiki Mizuki Takahashi Takahide Nishi 《Bioorganic & medicinal chemistry》2010,18(14):5346-5351
With the aim of exploring the effect of tricyclic-based FBPase inhibitors in cells and in vivo, a series of prodrugs of tricyclic phosphonates was designed and synthesized. Introducing prodrug moieties into tricyclic-based phosphonates led to the discovery of prodrug 15c, which strongly inhibited glucose production in monkey hepatocytes. Furthermore, prodrug 15c lowered blood glucose levels in fasted cynomolgus monkeys. 相似文献
7.
Paliwal S Reichard GA Shah S Wrobleski ML Wang C Stengone C Tsui HC Xiao D Duffy RA Lachowicz JE Nomeir AA Varty GB Shih NY 《Bioorganic & medicinal chemistry letters》2008,18(14):4168-4171
Strategic replacement of the nitrogen of the lead compound 1 in the original cyclic urea series with a carbon resulted in the discovery of a novel, potent and orally more efficacious γ-lactam series of selective NK1 antagonists. Optimization of the lactam series culminated in the identification of compounds with high binding affinity and excellent oral CNS activity. 相似文献
8.
Pinard E Alberati D Bender M Borroni E Brom V Burner S Fischer H Hainzl D Halm R Hauser N Jolidon S Lengyel J Marty HP Meyer T Moreau JL Mory R Narquizian R Norcross RD Schmid P Wermuth R Zimmerli D 《Bioorganic & medicinal chemistry letters》2010,20(23):6960-6965
Benzoylisoindolines were discovered as a novel structural class of GlyT1 inhibitors. SAR studies and subsequent lead optimization efforts focused primarily on addressing hERG liability and on improving in vivo efficacy resulted in the identification of potent GlyT1 inhibitors displaying excellent selectivity and in vivo PD and PK profiles. 相似文献
9.
《Bioorganic & medicinal chemistry》2014,22(15):4246-4256
We report herein the synthesis and structure–activity relationships (SAR) of a series of benzyl ether compounds as an S1P1 receptor modulator. From our SAR studies, the installation of substituents onto the central benzene ring of 2a was revealed to potently influence the S1P1 and S1P3 agonistic activities, in particular, an ethyl group on the 2-position afforded satisfactory S1P1/S1P3 selectivity. These changes of the S1P1 and S1P3 agonistic activities caused by the alteration of substituents on the 2-position were reasonably explained by a docking study using an S1P1 X-ray crystal structure and S1P3 homology modeling. We found that compounds 2b and 2e had a potent in vivo immunosuppressive efficacy along with acceptable S1P1/S1P3 selectivity, and confirmed that these compounds had less in vivo bradycardia risk through the evaluation of heart rate change after oral administration of the compounds (30 mg/kg, p.o.) in rats. 相似文献
10.
André Giroux Louise Boulet Christine Brideau Anh Chau David Claveau Bernard Côté Diane Ethier Richard Frenette Marc Gagnon Jocelyne Guay Sébastien Guiral Joseph Mancini Evelyn Martins Frédéric Massé Nathalie Méthot Denis Riendeau Joel Rubin Daigen Xu Hongping Yu Yves Ducharme Richard W. Friesen 《Bioorganic & medicinal chemistry letters》2009,19(20):5837-5841
Phenanthrene imidazoles 26 and 44 have been identified as novel potent, selective and orally active mPGES-1 inhibitors. These inhibitors are significantly more potent than the previously reported chlorophenanthrene imidazole 1 (MF63) with a human whole blood IC50 of 0.20 and 0.14 μM, respectively. It exhibited a significant analgesic effect in a guinea pig hyperalgesia model at oral doses as low as 14 mg/kg. Both active and selective mPGES-1 inhibitors (26 and 44) have a relatively distinct pharmacokinetic profile and are suitable for clinical development. 相似文献
11.
Stefano Crosignani Agnes Bombrun David Covini Maurizio Maio Delphine Marin Anna Quattropani Dominique Swinnen Don Simpson Wolfgang Sauer Bernard Françon Thierry Martin Yves Cambet Anthony Nichols Isabelle Martinou Fabienne Burgat-Charvillon Delphine Rivron Cristina Donini Olivier Schott Valerie Eligert Laurence Novo-Perez Jean-François Arrighi 《Bioorganic & medicinal chemistry letters》2010,20(5):1516-1519
The discovery of a novel series of S1P1 agonists is described. Starting from a micromolar HTS positive, iterative optimization gave rise to several single-digit nanomolar S1P1 agonists. The compounds were able to induce internalization of the S1P1 receptor, and a selected compound was shown to be able to induce lymphopenia in mice after oral dosing. 相似文献
12.
Colandrea VJ Legiec IE Huo P Yan L Hale JJ Mills SG Bergstrom J Card D Chebret G Hajdu R Keohane CA Milligan JA Rosenbach MJ Shei GJ Mandala SM 《Bioorganic & medicinal chemistry letters》2006,16(11):2905-2908
A series of 2,5-cis-disubstituted pyrrolidines were synthesized and evaluated as S1P receptor agonists. Compounds 15-21 were identified with good selectivity over S1P3 which lowered circulating lymphocytes after oral administration in mice. 相似文献
13.
Rainer Gewald Christian Grunwald Ute Egerland 《Bioorganic & medicinal chemistry letters》2013,23(15):4308-4314
Expanding on HTS hit 4 afforded a series of [1,3,5]triazine derivatives as novel PDE4 inhibitors. The SAR development and optimization process with the emphasis on ligand efficiency and physicochemical properties led to the discovery of compound 44 as a potent, selective and orally active PDE4 inhibitor. 相似文献
14.
Fujimoto T Kunitomo J Tomata Y Nishiyama K Nakashima M Hirozane M Yoshikubo S Hirai K Marui S 《Bioorganic & medicinal chemistry letters》2011,21(21):6414-6416
During our efforts to identify a series of potent, selective, orally active human Orexin-2 Receptor (OX2R) antagonists, we elucidated structure-activity relationship (SAR) on the 7-position of a benzoxazepine scaffold by utilizing Hammett σ(p) and Hansch-Fujita π value as aromatic substituent constants. The attempts led to the discovery of compound 1m, possessing good in vitro potency with over 100-fold selectivity against OX1R, good metabolic stability in human and rat liver microsome, good oral bioavailability in rats, and in vivo antagonistic activity in rats by oral administration. 相似文献
15.
Discovery of novel, potent, and orally active spiro-urea human glucagon receptor antagonists 总被引:4,自引:0,他引:4
Shen DM Zhang F Brady EJ Candelore MR Dallas-Yang Q Ding VD Dragovic J Feeney WP Jiang G McCann PE Mock S Qureshi SA Saperstein R Shen X Tamvakopoulos C Tong X Tota LM Wright MJ Yang X Zheng S Chapman KT Zhang BB Tata JR Parmee ER 《Bioorganic & medicinal chemistry letters》2005,15(20):4564-4569
A novel class of spiro-ureas has been discovered as potent human glucagon receptor antagonists in both binding and functional assays. Preliminary studies have revealed that compound 15 is an orally active human glucagon receptor antagonist in a transgenic murine pharmacodynamic model at 10 and 30 mpk. Compound 15 is orally bioavailable in several preclinical species and shows selectivity toward cardiac ion channels and other family B receptors, such as hGIP1 and hGLP. 相似文献
16.
Ratcliffe P Abernethy L Ansari N Cameron K Clarkson T Dempster M Dunn D Easson AM Edwards D Everett K Feilden H Ho KK Kultgen S Littlewood P Maclean J McArthur D McGregor D McLuskey H Neagu I Nimz O Nisbet LA Ohlmeyer M Palin R Pham Q Rong Y Roughton A Sammons M Swanson R Tracey H Walker G 《Bioorganic & medicinal chemistry letters》2011,21(15):4652-4657
Systematic optimisation of a poorly soluble lead series of isoxazole-3-carboxamides was conducted. Substitution of the 4-position with specific polar functionality afforded the requisite balance of potency, solubility and physicochemical properties. Compound 21a was found to be efficacious in the rat Capsaicin Hargreaves assay following oral administration. 相似文献
17.
Sinz C Chang J Lins AR Brady E Candelore M Dallas-Yang Q Ding V Jiang G Lin Z Mock S Qureshi S Salituro G Saperstein R Shang J Szalkowski D Tota L Vincent S Wright M Xu S Yang X Zhang B Tata J Kim R Parmee E 《Bioorganic & medicinal chemistry letters》2011,21(23):7131-7136
In the course of the development of an aminobenzimidazole class of human glucagon receptor (hGCGR) antagonists, a novel class of cyclic guanidine hGCGR antagonists was discovered. Rapid N-dealkylation resulted in poor pharmacokinetic profiles for the benchmark compound in this series. A strategy aimed at blocking oxidative dealkylation led to a series of compounds with improved rodent pharmacokinetic profiles. One compound was orally efficacious in a murine glucagon challenge pharmacodynamic model and also significantly lowered glucose levels in a murine diabetes model. 相似文献
18.
Shuwen He Zhixiong Ye Peter H. Dobbelaar Iyassu K. Sebhat Liangqin Guo Jian Liu Tianying Jian Yingjie Lai Christopher L. Franklin Raman K. Bakshi James P. Dellureficio Qingmei Hong Nancy N. Tsou Richard G. Ball Doreen E. Cashen William J. Martin David H. Weinberg Tanya MacNeil Rui Tang Constantin Tamvakopoulos Ravi P. Nargund 《Bioorganic & medicinal chemistry letters》2010,20(7):2106-2110
We report the design, synthesis and properties of spiroindane based compound 1, a potent, selective, orally bioavailable, non-peptide melanocortin subtype-4 receptor agonist. Compound 1 shows excellent erectogenic activity in the rodent models. 相似文献
19.
Noe MC Natarajan V Snow SL Wolf-Gouveia LA Mitchell PG Lopresti-Morrow L Reeves LM Yocum SA Otterness I Bliven MA Carty TJ Barberia JT Sweeney FJ Liras JL Vaughn M 《Bioorganic & medicinal chemistry letters》2005,15(14):3385-3388
A series of 3-hydroxy-3-methylpipecolic hydroxamate inhibitors of MMP-13 and aggrecanase was designed based on the observation of increased aggrecanase activity with substitution at the 3-position of the piperidine ring. Potency versus aggrecanase was optimized by modification of the benzyloxyarylsulfonamide group that binds in the S1' pocket. These compounds also possess markedly improved bioavailability and lower metabolic clearance compared to analogous 3,3-dimethyl-5-hydroxypipecolic hydroxamates. These improvements are attributed to lowered lipophilicity proximal to the metabolically labile hydroxamic acid. Synthesis, structure activity relationships, and in vivo efficacy data are described. 相似文献
20.
Li J Bertinato P Cheng H Cole BM Bronk BS Jaynes BH Hickman A Haven ML Kolosko NL Barry CJ Manion TB 《Bioorganic & medicinal chemistry letters》2006,16(11):3039-3042
We have successfully identified a number of novel MTP inhibitors with single digit nanomolar potency. Analogues 10aq and 10dq demonstrated in vivo efficacy in a murine gut retention assay. 相似文献