共查询到20条相似文献,搜索用时 15 毫秒
1.
《Bioorganic & medicinal chemistry》2016,24(16):3801-3807
Hormone sensitive lipase (HSL) is an attractive therapeutic target of dyslipidemia. We designed and synthesized several compounds as reversible HSL inhibitors with a focus on hydrophobic interactions, which was thought to be effective upon the HSL inhibitory activity. In these efforts, we identified boronated compound 12 showing a potent HSL inhibitory activity with an IC50 value of 7 nM and a high selectivity against cholinesterases. Furthermore, compound 12 is the first boron containing HSL inhibitor that has shown an antilipolytic effect in rats after oral administration at 3 mg/kg. 相似文献
2.
Yoshihiro Kato Motoji Kawasaki Tomohiro Nigo Shunya Nakamura Akira Fusano Yasuhiro Teranishi Mari N. Ito Takaaki Sumiyoshi 《Bioorganic & medicinal chemistry》2013,21(18):5851-5854
A series of 2,3-disubstituted pyridines were synthesized and evaluated for their PDE4 inhibitory activity. We successfully modified undesirable cyano group of initial lead compound 2 to 4-pyridyl group with improvement of in vitro efficacy and optimized the position of nitrogen atoms in pyridine moiety and alkylene linker. The most potent compound showed significant efficacy in animal models of asthma and inflammation. 相似文献
3.
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
4.
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
5.
Altenburger JM Lassalle GY Matrougui M Galtier D Jetha JC Bocskei Z Berry CN Lunven C Lorrain J Herault JP Schaeffer P O'Connor SE Herbert JM 《Bioorganic & medicinal chemistry》2004,12(7):1713-1730
SSR182289A 1 is the result of a rational optimisation process leading to an orally active thrombin inhibitor. The structure incorporates an original 2-(acetylamino)-[1,1'-biphenyl]-3-sulfonyl N-terminal motif, a central l-Arg surrogate carrying a weakly basic 3-amino-pyridine, and an unusual 4-difluoropiperidine at the C-terminus. Its synthesis is convergent and palladium catalysis has been employed for the construction of the key C-C bonds: Suzuki coupling for the bis-aryl fragment and Sonogashira reaction for the delta- bond of the central amino-acid chain. The compound is a potent inhibitor of thrombin's activities in vitro and demonstrates potent oral anti-thrombotic potencies in three rat models of thrombosis. The observed in vitro potency could be rationalized through the examination of the interactions within the SSR182289A 1 - thrombin crystal structure. SSR182289A 1, has been therefore selected for further development. 相似文献
6.
Zacharia S. Cheruvallath Stephen L. Gwaltney Mark Sabat Mingnam Tang Haixia Wang Andy Jennings David Hosfield Bumsup Lee Yiqin Wu Petro Halkowycz Charles E. Grimshaw 《Bioorganic & medicinal chemistry letters》2017,27(12):2678-2682
Guided by co-crystal structural information obtained from a different series we were exploring, a scaffold morphing and SBDD approach led to the discovery of the 1,4-disubstituted indazole series as a novel class of GKAs that potently activate GK in enzyme and cell assays. anti-diabetic OGTT efficacy was demonstrated with 29 in a rodent models of type 2 diabetes. 相似文献
7.
Takeshi Fukuda Riki Goto Toshihiro Kiho Kenjiro Ueda Sumie Muramatsu Masami Hashimoto Anri Aki Kengo Watanabe Naoki Tanaka 《Bioorganic & medicinal chemistry letters》2017,27(23):5252-5257
Hepcidin has emerged as the central regulatory molecule in systemic iron homeostasis, and its inhibition could be a favorable strategy for treating anemia of chronic disease (ACD). Here, we report the design, synthesis and structure–activity relationships (SAR) of a series of 4,6-disubstituted indazole compounds as hepcidin production inhibitors. The optimization study of multi-kinase inhibitor 1 led to the design of a potent and bioavailable hepcidin production inhibitor, 32 (DS28120313), which showed serum hepcidin-lowering effects in an interleukin-6-induced acute inflammatory mouse model. 相似文献
8.
Dumas J Hatoum-Mokdad H Sibley RN Smith RA Scott WJ Khire U Lee W Wood J Wolanin D Cooley J Bankston D Redman AM Schoenleber R Caringal Y Gunn D Romero R Osterhout M Paulsen H Housley TJ Wilhelm SM Pirro J Chien DS Ranges GE Shrikhande A Muzsi A Bortolon E Wakefield J Gianpaolo Ostravage C Bhargava A Chau T 《Bioorganic & medicinal chemistry letters》2002,12(12):1559-1562
Inhibitors of the MAP kinase p38 provide a novel approach for the treatment of osteoporosis, inflammatory disorders, and cancer. We have identified N-(3-tert-butyl-1-methyl-5-pyrazolyl)-N'-(4-(4-pyridinylmethyl)phenyl)urea as a potent and selective p38 kinase inhibitor in biochemical and cellular assays. This compound is orally active in two acute models of cytokine release (TNF-induced IL-6 and LPS-induced TNF) and a chronic model of arthritis (20-day murine collagen-induced arthritis). 相似文献
9.
Côté B Boulet L Brideau C Claveau D Ethier D Frenette R Gagnon M Giroux A Guay J Guiral S Mancini J Martins E Massé F Méthot N Riendeau D Rubin J Xu D Yu H Ducharme Y Friesen RW 《Bioorganic & medicinal chemistry letters》2007,17(24):6816-6820
Phenanthrene imidazole 3 (MF63) has been identified as a novel potent, selective, and orally active mPGES-1 inhibitor. This new series was developed by lead optimization of a hit from an internal HTS campaign. Compound 3 is significantly more potent than the previously reported indole carboxylic acid 1 with an A549 whole cell IC50 of 0.42 μM (50% FBS) and a human whole blood IC50 of 1.3 μM. It exhibited a significant analgesic effect in a guinea pig hyperalgesia model when orally dosed at 30 and 100 mg/kg. 相似文献
10.
Chen S Bartkovitz D Cai J Chen Y Chen Z Chu XJ Le K Le NT Luk KC Mischke S Naderi-Oboodi G Boylan JF Nevins T Qing W Chen Y Wovkulich PM 《Bioorganic & medicinal chemistry letters》2012,22(2):1247-1250
A series of pyrimidodiazepines was identified as potent Polo-like kinase 1 (PLK1) inhibitors. The synthesis and SAR are discussed. The lead compound 7 (RO3280) has potent inhibitory activity against PLK1, good selectivity against other kinases, and excellent in vitro cellular potency. It showed strong antitumor activity in xenograft mouse models. 相似文献
11.
Xie YF Lake K Ligsay K Komandla M Sircar I Nagarajan G Li J Xu K Parise J Schneider L Huang D Liu J Dines K Sakurai N Barbosa M Jack R 《Bioorganic & medicinal chemistry letters》2007,17(12):3367-3372
Design and synthesis of a series of 3-amino-4-(2-(2-(4-benzylpiperazin-1-yl)-2-oxoethoxy)phenylamino)cyclobutenedione derivatives as novel CCR1 antagonists are described. Structure-activity relationship studies led to the identification of compound 22, which demonstrated potent binding activity, functional antagonism of CCR1 as well as good species cross-reactivity. In addition, compound 22 also showed desirable pharmacokinetic profiles and was selected for in vivo studies in the mouse collagen-induced arthritis model. 相似文献
12.
Kinoshita K Asoh K Furuichi N Ito T Kawada H Hara S Ohwada J Miyagi T Kobayashi T Takanashi K Tsukaguchi T Sakamoto H Tsukuda T Oikawa N 《Bioorganic & medicinal chemistry》2012,20(3):1271-1280
Anaplastic lymphoma kinase (ALK) receptor tyrosine kinase is considered an attractive therapeutic target for human cancers, especially non-small cell lung cancer (NSCLC). Our previous study revealed that 8,9-side-chains of 6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole scaffold crucially affected kinase selectivity, cellular activity, and metabolic stability. In this work, we optimized the side-chains and identified highly selective, orally active and potent ALK inhibitor CH5424802 (18a) as the clinical candidate. 相似文献
13.
David Sperandio Vangelis Aktoudianakis Kerim Babaoglu Xiaowu Chen Kristyna Elbel Gregory Chin Britton Corkey Jinfa Du Bob Jiang Tetsuya Kobayashi Richard Mackman Ruben Martinez Hai Yang Jeff Zablocki Saritha Kusam Kim Jordan Heather Webb Jamie G. Bates David G. Breckenridge 《Bioorganic & medicinal chemistry》2019,27(3):457-469
14.
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
15.
Liang M Mallari C Rosser M Ng HP May K Monahan S Bauman JG Islam I Ghannam A Buckman B Shaw K Wei GP Xu W Zhao Z Ho E Shen J Oanh H Subramanyam B Vergona R Taub D Dunning L Harvey S Snider RM Hesselgesser J Morrissey MM Perez HD 《The Journal of biological chemistry》2000,275(25):19000-19008
The CC chemokine receptor-1 (CCR1) is a prime therapeutic target for treating autoimmune diseases. Through high capacity screening followed by chemical optimization, we identified a novel non-peptide CCR1 antagonist, R-N-[5-chloro-2-[2-[4-[(4-fluorophenyl)methyl]-2-methyl-1-piperazinyl ]-2-oxoethoxy]phenyl]urea hydrochloric acid salt (BX 471). Competition binding studies revealed that BX 471 was able to displace the CCR1 ligands macrophage inflammatory protein-1alpha (MIP-1alpha), RANTES, and monocyte chemotactic protein-3 (MCP-3) with high affinity (K(i) ranged from 1 nm to 5.5 nm). BX 471 was a potent functional antagonist based on its ability to inhibit a number of CCR1-mediated effects including Ca(2+) mobilization, increase in extracellular acidification rate, CD11b expression, and leukocyte migration. BX 471 demonstrated a greater than 10,000-fold selectivity for CCR1 compared with 28 G-protein-coupled receptors. Pharmacokinetic studies demonstrated that BX 471 was orally active with a bioavailability of 60% in dogs. Furthermore, BX 471 effectively reduces disease in a rat experimental allergic encephalomyelitis model of multiple sclerosis. This study is the first to demonstrate that a non-peptide chemokine receptor antagonist is efficacious in an animal model of an autoimmune disease. In summary, we have identified a potent, selective, and orally available CCR1 antagonist that may be useful in the treatment of chronic inflammatory diseases. 相似文献
16.
Egbertson MS Moritz HM Melamed JY Han W Perlow DS Kuo MS Embrey M Vacca JP Zrada MM Cortes AR Wallace A Leonard Y Hazuda DJ Miller MD Felock PJ Stillmock KA Witmer MV Schleif W Gabryelski LJ Moyer G Ellis JD Jin L Xu W Braun MP Kassahun K Tsou NN Young SD 《Bioorganic & medicinal chemistry letters》2007,17(5):1392-1398
A 1,6-naphthyridine inhibitor of HIV-1 integrase has been discovered with excellent inhibitory activity in cells, good pharmacokinetics, and an excellent ability to inhibit virus with mutant enzyme. 相似文献
17.
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
18.
Liddle J Atkinson FL Barker MD Carter PS Curtis NR Davis RP Douault C Dickson MC Elwes D Garton NS Gray M Hayhow TG Hobbs CI Jones E Leach S Leavens K Lewis HD McCleary S Neu M Patel VK Preston AG Ramirez-Molina C Shipley TJ Skone PA Smithers N Somers DO Walker AL Watson RJ Weingarten GG 《Bioorganic & medicinal chemistry letters》2011,21(20):6188-6194
The lead optimisation of the diaminopyrimidine carboxamide series of spleen tyrosine kinase inhibitors is described. The medicinal chemistry strategy was focused on optimising the human whole blood activity whilst achieving a sufficient margin over liability kinases and hERG activity. GSK143 is a potent and highly selective SYK inhibitor showing good efficacy in the rat Arthus model. 相似文献
19.
Ratcliffe P Maclean J Abernethy L Clarkson T Dempster M Easson AM Edwards D Everett K Feilden H Littlewood P McArthur D McGregor D McLuskey H Nimz O Nisbet LA Palin R Tracey H Walker G 《Bioorganic & medicinal chemistry letters》2011,21(8):2559-2563
Optimization of a water soluble, moderately potent lead series of isoxazole-3-carboxamides was conducted, affording a compound with the requisite balance of potency, solubility and physicochemical properties for in vivo use. Compound 8e was demonstrated to be efficacious in a rat model of inflammatory pain, following oral administration. 相似文献
20.
Ballard P Bradbury RH Hennequin LF Hickinson DM Johnson PD Kettle JG Klinowska T Morgentin R Ogilvie DJ Olivier A 《Bioorganic & medicinal chemistry letters》2005,15(19):4226-4229
Starting from a 6,7-substituted quinazoline lead 4, optimisation of 5-substituted quinazolines containing an extended aniline motif led to potent and selective inhibitors of erbB2 receptor tyrosine kinase, and a representative compound 12a inhibited tumour growth in a mouse xenograft model. 相似文献