共查询到20条相似文献,搜索用时 20 毫秒
1.
Guckian KM Lin EY Silvian L Friedman JE Chin D Scott DM 《Bioorganic & medicinal chemistry letters》2008,18(19):5249-5251
A series of meta-substituted anilines were designed and synthesized to inhibit the interaction of LFA-1 with ICAM for the treatment of autoimmune disease. Design of these molecules was performed by utilizing a co-crystal structure for structure-based drug design. The resulting molecules were found to be potent and to possess favorable pharmaceutical properties. 相似文献
2.
Alessandra Bartolozzi Asitha Abeywardane Todd Bosanac John A. Broadwater Zhidong Chen J. Matthew Hutzler John D. Huber Peter Nemoto Alan Olague Doris Riether Tom Simpson Hidenori Takahashi Lifen Wu Yunlong Zhang Renee M. Zindell 《Bioorganic & medicinal chemistry letters》2017,27(20):4652-4659
Structure activity relationship (SAR) investigation of an oxadiazole based series led to the discovery of several potent FLAP inhibitors. Lead optimization focused on achieving functional activity while improving physiochemical properties and reducing hERG inhibition. Several compounds with favorable in vitro and in vivo properties were identified that were suitable for advanced profiling. 相似文献
3.
Chen X Mihalic J Fan P Liang L Lindstrom M Wong S Ye Q Fu Y Jaen J Chen JL Dai K Li L 《Bioorganic & medicinal chemistry letters》2012,22(1):363-366
A series of spiropiperidine carbazoles were synthesized and evaluated as MCHR2 antagonists using a FLIPR assay. The pharmacokinetic properties of selected compounds have also been studied. This effort led to the discovery of potent and specific MCHR2 antagonists. Compound 38 demonstrated good pharmacokinetic properties across rat, beagle dog and rhesus monkey and had a favorable selectivity profile against a number of other receptors. These MCHR2 antagonists are considered appropriate tool compounds for study of the function of MCHR2 in vivo. 相似文献
4.
Carole Pissot-Soldermann Marc Gerspacher Pascal Furet Christoph Gaul Philipp Holzer Clive McCarthy Thomas Radimerski Catherine H. Regnier Fabienne Baffert Peter Drueckes Gisele A. Tavares Eric Vangrevelinghe Francesca Blasco Giorgio Ottaviani Flavio Ossola Julien Scesa Janitha Reetz 《Bioorganic & medicinal chemistry letters》2010,20(8):2609-2613
We have designed and synthesized a novel series of 2,8-diaryl-quinoxalines as Janus kinase 2 inhibitors. Many of the inhibitors show low nanomolar activity against JAK2 and potently suppress proliferation of SET-2 cells in vitro. In addition, compounds from this series have favorable rat pharmacokinetic properties suitable for in vivo efficacy evaluation. 相似文献
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Kap-Sun Yeung Zhilei Qiu Quifen Xue Haiquan Fang Zheng Yang Lisa Zadjura Celia J. D’Arienzo Betsy J. Eggers Keith Riccardi Pei-Yong Shi Yi-Fei Gong Marc R. Browning Qi Gao Steven Hansel Kenneth Santone Ping-Fang Lin Nicholas A. Meanwell John F. Kadow 《Bioorganic & medicinal chemistry letters》2013,23(1):198-202
A series of substituted carboxamides at the indole C7 position of the previously described 4-fluoro-substituted indole HIV-1 attachment inhibitor 1 was synthesized and the SAR delineated. Heteroaryl carboxamide inhibitors that exhibited pM potency in the primary cell-based assay against a pseudotype virus expressing a JRFL envelope were identified. The simple methyl amide analog 4 displayed a promising in vitro profile, with its favorable HLM stability and membrane permeability translating into favorable pharmacokinetic properties in preclinical species. 相似文献
7.
Xiong Y Ullman B Choi JS Cherrier M Strah-Pleynet S Decaire M Feichtinger K Frazer JM Yoon WH Whelan K Sanabria EK Grottick AJ Al-Shamma H Semple G 《Bioorganic & medicinal chemistry letters》2012,22(5):1870-1873
A series of fused bicyclic heterocycles was identified as potent and selective 5-HT(2A) receptor antagonists. Optimization of the series resulted in compounds that had improved PK properties, favorable CNS partitioning, good pharmacokinetic properties, and significant improvements on deep sleep (delta power) and sleep consolidation. 相似文献
8.
Cho A Zhang L Xu J Babusis D Butler T Lee R Saunders OL Wang T Parrish J Perry J Feng JY Ray AS Kim CU 《Bioorganic & medicinal chemistry letters》2012,22(12):4127-4132
A series of 2'-C-methyl branched purine and pyrimidine C-nucleosides were prepared. Their anti-HCV activity and pharmacological properties were profiled, and compared with known 2'-C-Me N-nucleoside counterparts. In particular, 2'-C-Me 4-aza-7,9-dideazaadenosine C-nucleoside (2) was found to have potent and selective anti-HCV activity in vitro as well as a favorable pharmacokinetic profile and in vivo potential for enhanced potency over the corresponding N-nucleoside. 相似文献
9.
Zhou D Gross JL Sze JY Adedoyin AB Bowlby M Di L Platt BJ Zhang G Brandon N Comery TA Robichaud AJ 《Bioorganic & medicinal chemistry letters》2011,21(19):5957-5960
On the basis of the previously reported benzimidazole 1,3'-bipyrrolidine benzamides (1), a series of related pyrrolidin-3-yl-N-methylbenzamides were synthesized and evaluated as H(3) receptor antagonists. In particular, compound 32 exhibits potent H(3) receptor binding affinity, improved pharmaceutical properties and a favorable in vivo profile. 相似文献
10.
Cai ZW Wei D Schroeder GM Cornelius LA Kim K Chen XT Schmidt RJ Williams DK Tokarski JS An Y Sack JS Manne V Kamath A Zhang Y Marathe P Hunt JT Lombardo LJ Fargnoli J Borzilleri RM 《Bioorganic & medicinal chemistry letters》2008,18(11):3224-3229
A series of acylurea analogs derived from pyrrolopyridine and aminopyridine scaffolds were identified as potent inhibitors of Met kinase activity. The SAR at various positions of the two kinase scaffolds was investigated. These studies led to the discovery of compounds 3b and 20b, which demonstrated favorable pharmacokinetic properties in mice and significant antitumor activity in a human gastric carcinoma xenograft model. 相似文献
11.
Ashley B. Forster Pravien Abeywickrema Jaime Bunda Christopher D. Cox Tamara D. Cabalu Melissa Egbertson John Fay Krista Getty Dawn Hall Maria Kornienko Jun Lu Gopal Parthasarathy John Reid Sujata Sharma William D. Shipe Sean M. Smith Stephen Soisson Shawn J. Stachel Richard Berger 《Bioorganic & medicinal chemistry letters》2017,27(23):5167-5171
We have identified a novel PDE2 inhibitor series using fragment-based screening. Pyrazolopyrimidine fragment 1, while possessing weak potency (Ki?=?22.4?μM), exhibited good binding efficiencies (LBE?=?0.49, LLE?=?4.48) to serve as a start for structure-based drug design. With the assistance of molecular modeling and X-ray crystallography, this fragment was developed into a series of potent PDE2 inhibitors with good physicochemical properties. Compound 16, a PDE2 selective inhibitor, was identified that exhibited favorable rat pharmacokinetic properties. 相似文献
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13.
DeMarco SJ Henze H Lederer A Moehle K Mukherjee R Romagnoli B Robinson JA Brianza F Gombert FO Lociuro S Ludin C Vrijbloed JW Zumbrunn J Obrecht JP Obrecht D Brondani V Hamy F Klimkait T 《Bioorganic & medicinal chemistry》2006,14(24):8396-8404
Novel highly potent CXCR4 inhibitors with good pharmacokinetic properties were designed and optimized starting from the naturally occurring β-hairpin peptide polyphemusin II. The design involved incorporating important residues from polyphemusin II into a macrocyclic template-bound β-hairpin mimetic. Using a parallel synthesis approach, the potency and ADME properties of the mimetics were optimized in iterative cycles, resulting in the CXCR4 inhibitors POL2438 and POL3026. The inhibitory potencies of these compounds were confirmed in a series of HIV-1 invasion assays in vitro. POL3026 showed excellent plasma stability, high selectivity for CXCR4, favorable pharmacokinetic properties in the dog, and thus has the potential to become a therapeutic compound for application in the treatment of HIV infections (as an entry inhibitor), cancer (for angiogenesis suppression and inhibition of metastasis), inflammation, and in stem cell transplant therapy. 相似文献
14.
Bryan MC Biswas K Peterkin TA Rzasa RM Arik L Lehto SG Sun H Hsieh FY Xu C Fremeau RT Allen JR 《Bioorganic & medicinal chemistry letters》2012,22(1):619-622
A series of fused 6,6-bicyclic chromenones was investigated for activity against the bradykinin B1 receptor. SAR studies based on a pharmacophore model revealed compounds with high affinity for both human and rabbit B1. These compounds demonstrated favorable pharmacokinetic properties and 5-chlorochromenone 15 was efficacious in a carrageenan-induced mechanical hyperalgesia model for chronic pain. 相似文献
15.
《MABS-AUSTIN》2013,5(3):505-515
The application of monoclonal antibodies as commercial therapeutics poses substantial demands on stability and properties of an antibody. Therapeutic molecules that exhibit favorable properties increase the success rate in development. However, it is not yet fully understood how the protein sequences of an antibody translates into favorable in vitro molecule properties. In this work, computational design strategies based on heuristic sequence analysis were used to systematically modify an antibody that exhibited a tendency to precipitation in vitro. The resulting series of closely related antibodies showed improved stability as assessed by biophysical methods and long-term stability experiments. As a notable observation, expression levels also improved in comparison with the wild-type candidate. The methods employed to optimize the protein sequences, as well as the biophysical data used to determine the effect on stability under conditions commonly used in the formulation of therapeutic proteins, are described. Together, the experimental and computational data led to consistent conclusions regarding the effect of the introduced mutations. Our approach exemplifies how computational methods can be used to guide antibody optimization for increased stability. 相似文献
16.
Daniel Seeliger Patrick Schulz Tobias Litzenburger Julia Spitz Stefan Hoerer Michaela Blech Barbara Enenkel Joey M Studts Patrick Garidel Anne R Karow 《MABS-AUSTIN》2015,7(3):505-515
The application of monoclonal antibodies as commercial therapeutics poses substantial demands on stability and properties of an antibody. Therapeutic molecules that exhibit favorable properties increase the success rate in development. However, it is not yet fully understood how the protein sequences of an antibody translates into favorable in vitro molecule properties. In this work, computational design strategies based on heuristic sequence analysis were used to systematically modify an antibody that exhibited a tendency to precipitation in vitro. The resulting series of closely related antibodies showed improved stability as assessed by biophysical methods and long-term stability experiments. As a notable observation, expression levels also improved in comparison with the wild-type candidate. The methods employed to optimize the protein sequences, as well as the biophysical data used to determine the effect on stability under conditions commonly used in the formulation of therapeutic proteins, are described. Together, the experimental and computational data led to consistent conclusions regarding the effect of the introduced mutations. Our approach exemplifies how computational methods can be used to guide antibody optimization for increased stability. 相似文献
17.
Hom RK Bowers S Sealy JM Truong AP Probst GD Neitzel ML Neitz RJ Fang L Brogley L Wu J Konradi AW Sham HL Tóth G Pan H Yao N Artis DR Quinn K Sauer JM Powell K Ren Z Bard F Yednock TA Griswold-Prenner I 《Bioorganic & medicinal chemistry letters》2010,20(24):7303-7307
From high throughput screening, we discovered compound 1, the prototype for a series of disubstituted thiophene inhibitors of JNK which is selective towards closely related MAP kinases p38 and Erk2. Herein we describe the evolution of these compounds to a novel class of thiophene and thiazole JNK inhibitors that retain favorable solubility, permeability, and P-gp properties for development as CNS agents for treatment of neurodegeneration. Compound 61 demonstrated JNK3 IC(50)=77 nM and retained the excellent broad kinase selectivity observed for the series. 相似文献
18.
《Bioorganic & medicinal chemistry letters》2014,24(14):3199-3203
A series of TRPA1 antagonists is described having a 4-aryloxy-1H-pyrrolo[3,2-c]pyridine or a 1-aryloxyisoquinoline scaffold. These compounds have high ligand efficiency and favorable physical properties and may thus serve as scaffolds for further optimization. 相似文献
19.
肝细胞靶向pH敏脂质体的制备及性质分析 总被引:3,自引:0,他引:3
为了制备具有肝细胞特异靶向性和pH敏感性的脂质体,设计并合成了四种带有半乳糖残基的导向分子,与具有pH敏感性的DC-chol/DOPE混合制备脂质体,通过质粒转染实验、受体竞争抑制实验和红细胞溶血等实验选出最佳转染活性的十八醇-半乳糖甙(18-gal)脂质体,并证明其具有肝细胞特异受体介导的靶向性和pH敏感性,且细胞毒性较小,可以作为一种潜在的肝细胞靶向转运系统得到进一步发展. 相似文献
20.
Joel T. Arcari Jean S. Beebe Martin A. Berliner Vincent Bernardo Merin Boehm Gary V. Borzillo Tracey Clark Bruce D. Cohen Richard D. Connell Heather N. Frost Deborah A. Gordon William M. Hungerford Shefali M. Kakar Aaron Kanter Nandell F. Keene Elizabeth A. Knauth Susan D. LaGreca Yong Lu Jinshan M. Chen 《Bioorganic & medicinal chemistry letters》2013,23(10):3059-3063
The synthesis and biological evaluation of novel Tie-2 kinase inhibitors are presented. Based on the pyrrolopyrimidine chemotype, several new series are described, including the benzimidazole series by linking a benzimidazole to the C5-position of the 4-amino-pyrrolopyrimidine core and the ketophenyl series synthesized by incorporating a ketophenyl group to the C5-position. Medicinal chemistry efforts led to potent Tie-2 inhibitors. Compound 15, a ketophenyl pyrrolopyrimidine urea analog with improved physicochemical properties, demonstrated favorable in vitro attributes as well as dose responsive and robust oral tumor growth inhibition in animal models. 相似文献