共查询到20条相似文献,搜索用时 15 毫秒
1.
Kenji Naganuma Akifumi Omura Naomi Maekawara Masahiro Saitoh Naoto Ohkawa Takashi Kubota Hiromitsu Nagumo Toshiyuki Kodama Masayoshi Takemura Yuji Ohtsuka Junji Nakamura Ryuichi Tsujita Koh Kawasaki Hirotsugu Yokoi Masashi Kawanishi 《Bioorganic & medicinal chemistry letters》2009,19(12):3174-3176
In this study the first PDE4B selective inhibitor is described. Optimization of lead 2-arylpyrimidine derivatives afforded a series of potent PDE4B inhibitors with >100-fold selectivity over the PDE4D isozyme. With a good pharmacokinetic profile, a selected compound exhibited potent anti-inflammatory effects in vivo and showed less emesis compared with Cilomilast. 相似文献
2.
Pauline C. Ting Joe F. Lee Rongze Kuang Jianhua Cao Danlin Gu Ying Huang Zhidan Liu Robert G. Aslanian Kung-I. Feng Daniel Prelusky James Lamca Aileen House Jonathan E. Phillips Peng Wang Ping Wu Daniel Lundell Richard W. Chapman Chander S. Celly 《Bioorganic & medicinal chemistry letters》2013,23(20):5528-5532
The optimization of oxazole-based PDE4 inhibitor 1 has led to the identification of both oral (compound 16) and inhaled (compound 34) PDE4 inhibitors. Selectivity against PDE10/PDE11, off target screening, and in vivo activity in the rat are discussed. 相似文献
3.
《Bioorganic & medicinal chemistry letters》2014,24(16):4031-4034
In this study we report a series of triazine derivatives that are potent inhibitors of PDE4B. We also provide a series of structure activity relationships that demonstrate the triazine core can be used to generate subtype selective inhibitors of PDE4B versus PDE4D. A high resolution co-crystal structure shows that the inhibitors interact with a C-terminal regulatory helix (CR3) locking the enzyme in an inactive ‘closed’ conformation. The results show that the compounds interact with both catalytic domain and CR3 residues. This provides the first structure-based approach to engineer PDE4B-selective inhibitors. 相似文献
4.
Kuang R Shue HJ Xiao L Blythin DJ Shih NY Chen X Gu D Schwerdt J Lin L Ting PC Cao J Aslanian R Piwinski JJ Prelusky D Wu P Zhang J Zhang X Celly CS Billah M Wang P 《Bioorganic & medicinal chemistry letters》2012,22(7):2594-2597
Optimization of oxazole-based PDE4 inhibitors has led to the discovery of a series of quinolyl oxazoles, with 4-benzylcarboxamide and 5-α-aminoethyl groups which exhibit picomolar potency against PDE4. Selectivity profiles and in vivo biological activity are also reported. 相似文献
5.
Bauer U Giordanetto F Bauer M O'Mahony G Johansson KE Knecht W Hartleib-Geschwindner J Carlsson ET Enroth C 《Bioorganic & medicinal chemistry letters》2012,22(5):1944-1948
A series of 1,6-naphthyridine-based compounds was synthesized as potent phosphodiesterase 10A (PDE10A) inhibitors. Structure-based chemical modifications of the discovered chemotype served to further improve potency and selectivity over DHODH, laying the foundation for future optimization efforts. 相似文献
6.
Irvine MW Patrick GL Kewney J Hastings SF MacKenzie SJ 《Bioorganic & medicinal chemistry letters》2008,18(6):2032-2037
The discovery, synthesis and in vitro activity of a novel series of rhodanine based phosphodiesterase-4 (PDE4) inhibitors is described. Structure-activity relationship studies directed toward improving potency led to the development of submicromolar inhibitors 2n and 3i (IC(50)=0.89 & 0.74 microM). The replacement of rhodanine with structurally related heterocycles was also investigated and led to the synthesis of pseudothiohydantoin 7 (IC(50)=0.31 microM). 相似文献
7.
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
8.
Leyi Gong Yun-Chou Tan Genevieve Boice Sarah Abbot Kristen McCaleb Pravin Iyer Fengrong Zuo Joseph Dal Porto Brian Wong Sue Jin Alice Chang Patricia Tran Gary Hsieh Linghao Niu Ada Shao Deborah Reuter Christine M. Lukacs R. Ursula Kammlott Andreas Kuglstatter David Goldstein 《Bioorganic & medicinal chemistry letters》2012,22(24):7381-7387
A novel series of highly selective JNK inhibitors based on the 4-quinolone scaffold was designed and synthesized. Structure based drug design was utilized to guide the compound design as well as improvements in the physicochemical properties of the series. Compound (13c) has an IC50 of 62/170 nM for JNK1/2, excellent kinase selectivity and impressive efficacy in a rodent asthma model. 相似文献
9.
John Porter Simon Lumb Richard J. Franklin Jose M. Gascon-Simorte Mark Calmiano Kelly Le Riche Bénédicte Lallemand Jean Keyaerts Helen Edwards Alison Maloney Jean Delgado Lloyd King Anne Foley Fabien Lecomte James Reuberson Christoph Meier Mark Batchelor 《Bioorganic & medicinal chemistry letters》2009,19(10):2780-2784
A series of 4-azaindole inhibitors of c-Met kinase is described. The postulated binding mode was confirmed by an X-ray crystal structure and series optimisation was performed on the basis of this structure. Future directions for series development are discussed. 相似文献
10.
Sunghyun Kang Hye-Jin Min Min-Seo Kang Myung-Geun Jung Semi Kim 《Bioorganic & medicinal chemistry letters》2013,23(6):1748-1751
TMPRSS4 is a novel type II transmembrane serine protease that has been implicated in the invasion and metastasis of colon cancer cells. In this study, a novel series of 2-hydroxydiarylamide derivatives were synthesized and evaluated for inhibiting TMPRSS4 serine protease activity and suppressing cancer cell invasion. These derivatives demonstrated good inhibitory activity against TMPRSS4 serine protease, which correlated with the promising anti-invasive activity of colon cancer cells overexpressing TMPRSS4. 相似文献
11.
Billah M Buckley GM Cooper N Dyke HJ Egan R Ganguly A Gowers L Haughan AF Kendall HJ Lowe C Minnicozzi M Montana JG Oxford J Peake JC Picken CL Piwinski JJ Naylor R Sabin V Shih NY Warneck JB 《Bioorganic & medicinal chemistry letters》2002,12(12):1617-1619
The synthesis and pharmacological profile of a novel series of 2-substituted 8-methoxyquinolines is described. The 2-trifluoromethyl compound was found to be a potent inhibitor of phosphodiesterase type 4 (PDE4). 相似文献
12.
D G McGarry J R Regan F A Volz C Hulme K J Moriarty S W Djuric J E Souness B E Miller J J Travis D M Sweeney 《Bioorganic & medicinal chemistry》1999,7(6):1131-1139
Replacement of the 3,4-dialkoxyphenyl substructure common to a number of PDE4 inhibitors with a 2-alkyl-7-methoxybenzofuran unit is described. This substitution can result in either enhancement or substantial reductions in PDE4 inhibitory activity depending on the system to which it is applied. An in vitro SAR study of a potent series of 4-(2-heteroaryl-ethyl)-benzoiurans 26 is also presented. 相似文献
13.
Yvonne R. Freund Tsutomu Akama M.R.K. Alley Joana Antunes Chen Dong Kurt Jarnagin Richard Kimura James A. Nieman Kirk R. Maples Jacob J. Plattner Fernando Rock Rashmi Sharma Rajeshwar Singh Virginia Sanders Yasheen Zhou 《FEBS letters》2012,586(19):3410-3414
We have used boron-based molecules to create novel, competitive, reversible inhibitors of phosphodiesterase 4 (PDE4). The co-crystal structure reveals a binding configuration which is unique compared to classical catechol PDE4 inhibitors, with boron binding to the activated water in the bimetal center. These phenoxybenzoxaboroles can be optimized to generate submicromolar potency enzyme inhibitors, which inhibit TNF-α, IL-2, IFN-γ, IL-5 and IL-10 activities in vitro and show safety and efficacy for topical treatment of human psoriasis. They provide a valuable new route for creating novel potent anti-PDE4 inhibitors. 相似文献
14.
Hamblin JN Angell TD Ballantine SP Cook CM Cooper AW Dawson J Delves CJ Jones PS Lindvall M Lucas FS Mitchell CJ Neu MY Ranshaw LE Solanke YE Somers DO Wiseman JO 《Bioorganic & medicinal chemistry letters》2008,18(14):4237-4241
Optimisation of a high-throughput screening hit resulted in the discovery of 4-(substituted amino)-1-alkyl-pyrazolo[3,4-b]pyridine-5-carboxamides as potent and selective inhibitors of Phosphodiesterase 4 (PDE4). Herein, we describe early SAR studies around this novel template highlighting preferred substituents and rationalization of SAR through X-ray crystal structures of analogues bound to the PDE4 active site. Pyrazolopyridine 20a was found to be a potent and selective PDE4 inhibitor which also inhibits LPS induced TNF-α production from isolated human peripheral blood mononuclear cells and has an encouraging rat PK profile suitable for oral dosing. 相似文献
15.
Pascal Y Andrianjara CR Auclair E Avenel N Bertin B Calvet A Féru F Lardon S Moodley I Ouagued M Payne A Pruniaux MP Szilagyi C 《Bioorganic & medicinal chemistry letters》2000,10(1):35-38
A novel series of benzodiazepine derivatives have been discovered as inhibitors of PDE4 enzymes. We have found that our compounds are selective versus other PDE enzymes, and that the activity can be modulated by specific structural modifications. One compound exhibited a strong eosinophilic infiltration inhibiting action on sensitized Brown-Norway rats (compound 9, 5.1 mg/kg p.o.), moreover this compound is not emetic at 3 mg/kg i.v. 相似文献
16.
The next generation of PDE4 inhibitors 总被引:6,自引:0,他引:6
A number of highly potent PDE4 inhibitors are being developed for the treatment of asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, multiple sclerosis and Crohn's disease. Cilomilast (Ariflo, SB 207499, SmithKline Beecham), the most advanced member of the class in Phase III clinical trials, was reported to have a limited therapeutic window. Other inhibitors with improved profiles in preclinical models are entering into (or are in) clinical trials. The recent developments in understanding PDE4 catalysis, inhibitor binding and their emetic response should facilitate the design of the next generation of PDE4 inhibitors. 相似文献
17.
Mark S. Plummer Joseph Cornicelli Howard Roark Donald J. Skalitzky Charles J. Stankovic Susan Bove Jayvardhan Pandit Annise Goodman James Hicks Aurash Shahripour David Beidler Xiao Kang Lu Brian Sanchez Christopher Whitehead Ron Sarver Timothy Braden Richard Gowan Xi Qiang Shen Sandra Lightle 《Bioorganic & medicinal chemistry letters》2013,23(11):3438-3442
We identified potent, selective PDE2 inhibitors by optimizing residual PDE2 activity in a series of PDE4 inhibitors, while simultaneously minimizing PDE4 activity. These newly designed PDE2 inhibitors bind to the PDE2 enzyme in a cGMP-like mode in contrast to the cAMP-like binding mode found in PDE4. Structure activity relationship studies coupled with an inhibitor bound crystal structure in the active site of the catalytic domain of PDE2 identified structural features required to minimize PDE4 inhibition while simultaneously maximizing PDE2 inhibition. 相似文献
18.
Sai Li Yanfang Zhao Kewen Wang Yali Gao Jianming Han Bingbing Cui Ping Gong 《Bioorganic & medicinal chemistry》2013,21(11):2843-2855
A series of novel 4-(2-fluorophenoxy)quinoline derivatives containing 4-oxo-1,4-dihydrocinnoline-3-carboxamide moiety were designed, synthesized and evaluated for their in vitro biological activities against c-Met kinase and six typical cancer cell lines (A549, H460, HT-29, MKN-45, U87MG and SMMC-7721). All the prepared compounds showed moderate to excellent antiproliferative activity, and the analysis of their structure–activity relationships indicated that 2-chloro or 2-trifluoromethyl substituted phenyl group on the 1-position of cinnoline ring was more favorable for antitumor activity. In this study, a promising compound 33, with a c-Met IC50 value of 0.59 nM, was identified as a multitargeted receptor tyrosine kinase inhibitor. 相似文献
19.
Wang D Deng C Bugaj-Gaweda B Kwan M Gunwaldsen C Leonard C Xin X Hu Y Unterbeck A De Vivo M 《Cellular signalling》2003,15(9):883-891
20.
Taiji Goto Akiko Shiina Toshiharu Yoshino Kiyoshi Mizukami Kazuki Hirahara Osamu Suzuki Yoshitaka Sogawa Tomoko Takahashi Tsuyoshi Mikkaichi Naoki Nakao Mizuki Takahashi Masashi Hasegawa Shigeki Sasaki 《Bioorganic & medicinal chemistry letters》2013,23(11):3325-3328
2-Phenyl-4-piperidinyl-6,7-dihydrothieno[3,4-d]pyrimidine derivative (2) was found to be a new PDE4 inhibitor with moderate PDE4B activity (IC50 = 150 nM). A number of derivatives with a variety of 4-amino substituents and fused bicyclic pyrimidines were synthesized. Among these, 5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivative (18) showed potent PDE4B inhibitory activity (IC50 = 25 nM). Finally, N-propylacetamide derivative (31b) was determined as a potent inhibitor for both PDE4B (IC50 = 7.5 nM) and TNF-α production in mouse splenocytes (IC50 = 9.8 nM) and showed good in vivo anti-inflammatory activity in the LPS-induced lung inflammation model in mice (ID50 = 18 mg/kg). The binding mode of the new inhibitor (31e) in the catalytic site of PDE4B is presented based on an X-ray crystal structure of the ligand–enzyme complex. 相似文献