共查询到20条相似文献,搜索用时 812 毫秒
1.
Travins JM Ali F Huang H Ballentine SK Khalil E Hufnagel HR Pan W Gushue J Leonard K Bone RF Soll RM DesJarlais RL Crysler CS Ninan N Kirkpatrick J Cummings MD Huebert N Molloy CJ Gaul M Tomczuk BE Subasinghe NL 《Bioorganic & medicinal chemistry letters》2008,18(5):1603-1606
Complement activation has been implicated in disease states such as hereditary angioedema, ischemia-reperfusion injury, acute respiratory distress syndrome, and acute transplant rejection. Even though the complement cascade provides several protein targets for potential therapeutic intervention only two complement inhibitors have been approved so far for clinical use including anti-C5 antibodies for the treatment of paroxysmal nocturnal hemoglobinuria and purified C1-esterase inhibitor replacement therapy for the control of hereditary angioedema flares. In the present study, optimization of potency and physicochemical properties of a series of thiophene amidine-based C1s inhibitors with potential utility as intravenous agents for the inhibition of the classical pathway of complement is described. 相似文献
2.
Olivier Venier Cécile Pascal Alain Braun Claudie Namane Patrick Mougenot Olivier Crespin François Pacquet Cécile Mougenot Catherine Monseau Bénédicte Onofri Rommel Dadji-Faïhun Céline Leger Majdi Ben-Hassine Thao Van-Pham Jean-Luc Ragot Christophe Philippo Géraldine Farjot Lionel Noah Antonio Castro 《Bioorganic & medicinal chemistry letters》2013,23(8):2414-2421
Starting from 11β-HSD1 inhibitors that were active ex vivo but with Cyp 3A4 liability, we obtained a new series of adamantane ureas displaying potent inhibition of both human and rodent 11β-HSD1 enzymes, devoid of Cyp 3A4 interactions, and rationally designed to provide long-lasting inhibition in target tissues. Final optimizations lead to SAR184841 with good oral pharmacokinetic properties showing in vivo activity and improvement of metabolic parameters in a physiopathological model of type 2 diabetes. 相似文献
3.
Keith R. Hornberger Xin Chen Andrew P. Crew Andrew Kleinberg Lifu Ma Mark J. Mulvihill Jing Wang Victoria L. Wilde Mark Albertella Mark Bittner Andrew Cooke Salam Kadhim Jennifer Kahler Paul Maresca Earl May Peter Meyn Darlene Romashko Brianna Tokar Roy Turton 《Bioorganic & medicinal chemistry letters》2013,23(16):4511-4516
The kinase selectivity and pharmacokinetic optimization of a series of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1 is described. The intersection of insights from molecular modeling, computational prediction of metabolic sites, and in vitro metabolite identification studies resulted in a simple and unique solution to both of these problems. These efforts culminated in the discovery of compound 13a, a potent, relatively selective inhibitor of TAK1 with good pharmacokinetic properties in mice, which was active in an in vivo model of ovarian cancer. 相似文献
4.
Koo KD Kim MJ Kim S Kim KH Hong SY Hur GC Yim HJ Kim GT Han HO Kwon OH Kwon TS Koh JS Lee CS 《Bioorganic & medicinal chemistry letters》2007,17(15):4167-4172
Synthesis of a novel series of DPPIV inhibitors with 1,2,4- and 1,3,4-oxadiazolyl ketone derivatives and its structure-activity relationships are discussed. Compound 18h showed good inhibitory activity against DPPIV and favorable pharmacokinetic properties. In vivo pharmacodynamic efficacy and co-crystal structure of compound 18h with DPPIV is also described. 相似文献
5.
Cockcroft XL Dillon KJ Dixon L Drzewiecki J Kerrigan F Loh VM Martin NM Menear KA Smith GC 《Bioorganic & medicinal chemistry letters》2006,16(4):1040-1044
We have previously described the discovery of poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors based on a phthalazinone scaffold. Subsequent optimisation of inhibitory activity, metabolic stability and pharmacokinetic parameters has led to a novel series of meta-substituted 4-benzyl-2H-phthalazin-1-one PARP-1 inhibitors which retain low nM cellular activity and show good stability in vivo and efficacy in cell based models. 相似文献
6.
Epple R Azimioara M Russo R Xie Y Wang X Cow C Wityak J Karanewsky D Bursulaya B Kreusch A Tuntland T Gerken A Iskandar M Saez E Martin Seidel H Tian SS 《Bioorganic & medicinal chemistry letters》2006,16(21):5488-5492
A series of PPARdelta-selective agonists was investigated and optimized for a favorable in vivo pharmacokinetic profile. Isoxazole LCI765 (17d) was found to be a potent and selective PPARdelta agonist with good in vivo PK properties in mouse (C(max)=5.1 microM, t(1/2)=3.1 h). LCI765 regulated expression of genes involved in energy homeostasis in relevant tissues when dosed orally in C57BL6 mice. A co-crystal structure of compound LCI765 and the LBD of PPARdelta is discussed. 相似文献
7.
Scott DA Aquila BM Bebernitz GA Cook DJ Dakin LA Deegan TL Hattersley MM Ioannidis S Lyne PD Omer CA Ye M Zheng X 《Bioorganic & medicinal chemistry letters》2008,18(17):4794-4797
The bisamide class of kinase inhibitors was identified as being active against CSF-1R. The synthesis and SAR of pyridyl and thiazolyl bisamides are reported, along with the pharmacokinetic properties and in vivo activity of selected examples. 相似文献
8.
Andrew M. Haidle Kaleen K. Childers Anna A. Zabierek Jason D. Katz James P. Jewell Yongquan Hou Michael D. Altman Alexander Szewczak Dapeng Chen Andreas Harsch Mansuo Hayashi Lee Warren Michael Hutton Hugh Nuthall Matt G. Stanton Ian W. Davies Ben Munoz Alan Northrup 《Bioorganic & medicinal chemistry letters》2017,27(1):109-113
Attempts to optimize pharmacokinetic properties in a promising series of pyrrolopyrimidinone MARK inhibitors for the treatment of Alzheimer’s disease are described. A focus on physical properties and ligand efficiency while prosecuting this series afforded key tool compounds that revealed a large discrepancy in the rat in vitro–in vivo DMPK (Drug Metabolism/Pharmacokinetics) correlation. These differences prompted an in vivo rat disposition study employing a radiolabeled representative of the series, and the results from this experiment justified the termination of any further optimization efforts. 相似文献
9.
Becknell NC Zulli AL Angeles TS Yang S Albom MS Aimone LD Robinson C Chang H Hudkins RL 《Bioorganic & medicinal chemistry letters》2006,16(20):5368-5372
A novel series of C-3 urea, amide, and carbamate fused dihydroindazolocarbazole (DHI) analogs are reported as highly potent dual inhibitors of TIE-2 and VEGF-R2 receptor tyrosine kinases with excellent cellular potency. Structure-activity relationship (SAR) studies indicate the optimal N-13 alkyl substitutions are n-propyl and i-butyl. The isopropyl carbamate 39 displayed good dual enzyme, cell potency, and rat pharmacokinetic properties for advancement to in vivo evaluation. 相似文献
10.
Barrett DG Boncek VM Catalano JG Deaton DN Hassell AM Jurgensen CH Long ST McFadyen RB Miller AB Miller LR Payne JA Ray JA Samano V Shewchuk LM Tavares FX Wells-Knecht KJ Willard DH Wright LL Zhou HQ 《Bioorganic & medicinal chemistry letters》2005,15(15):3540-3546
An orally bioavailable series of ketoamide-based cathepsin K inhibitors with good pharmacokinetic properties has been identified. Starting from a potent inhibitor endowed with poor drug properties, conformational constraint of the P(2)-P(3) linker and modifications to P(1') elements led to an enhancement in potency, solubility, clearance, and bioavailability. These optimized inhibitors attenuated bone resorption in a rat TPTX hypocalcemic bone resorption model. 相似文献
11.
Janser P Neumann U Miltz W Feifel R Buhl T 《Bioorganic & medicinal chemistry letters》2006,16(10):2632-2636
The structural features contributing to the different pharmacokinetic properties of the TACE/MMP inhibitors TNF484 and Trocade were analyzed using an in vivo cassette-dosing approach in rats. This enabled us to identify a new lead compound with excellent pharmacokinetic properties, but weaker activity on the biological targets. Directed structural modifications maintained oral bioavailability and restored biological activity, leading to a novel compound almost equipotent to TNF484 in vivo, but with a more than tenfold higher oral bioavailability. 相似文献
12.
Adkison KK Barrett DG Deaton DN Gampe RT Hassell AM Long ST McFadyen RB Miller AB Miller LR Payne JA Shewchuk LM Wells-Knecht KJ Willard DH Wright LL 《Bioorganic & medicinal chemistry letters》2006,16(4):978-983
Starting from potent aldehyde inhibitors with poor drug properties, derivatization to semicarbazones led to the identification of a series of semicarbazone-based cathepsin K inhibitors with greater solubility and better pharmacokinetic profiles than their parent aldehydes. Furthermore, a representative semicarbazone inhibitor attenuated bone resorption in an ex vivo rat calvarial bone resorption model. However, based on enzyme inhibition comparisons at neutral pH, semicarbazone hydrolysis rates, and 13C NMR experiments, these semicarbazones probably function as prodrugs of aldehydes. 相似文献
13.
Tetsuyoshi Matsufuji Mika Ikeda Asuka Naito Masakazu Hirouchi Shoichi Kanda Masanori Izumi Jun Harada Tsuyoshi Shinozuka 《Bioorganic & medicinal chemistry letters》2013,23(9):2560-2565
The discovery and optimization of a novel series of FATP1 inhibitors are described. Through the derivatization process, arylpiperazine derivatives 5k and 12a were identified as possessing potent in vitro activity against human and mouse FATP1s as well as excellent pharmacokinetic properties. In vivo evaluation of triglyceride accumulation in the liver, white gastrocnemius muscle and soleus is also described. 相似文献
14.
Jones CD Andrews DM Barker AJ Blades K Byth KF Finlay MR Geh C Green CP Johannsen M Walker M Weir HM 《Bioorganic & medicinal chemistry letters》2008,18(24):6486-6489
The development of a novel series of imidazole pyrimidine amides as cyclin-dependent kinase (CDK) inhibitors is described. The series was found to have much improved CDK2 inhibition and potent in vitro anti-proliferative effects against cancer cell lines. Control of overall lipophilicity was important to achieve good in vitro potency along with acceptable physiochemical properties and margins against inhibition of both CYP isoforms and the hERG potassium ion channel. A compound with an attractive overall balance of properties was profiled in vivo and possessed suitable physiochemical and pharmacokinetic profiles for oral dosing. 相似文献
15.
《Bioorganic & medicinal chemistry》2014,22(4):1429-1440
A novel series of Hh signaling pathway inhibitors were designed by replacing the pyrimidine skeleton of our earlier reported lead compound 1 with pyrrolo[2,1-f][1,2,4]triazine scaffold. Starting from this new scaffold, SAR exploration was investigated based on structural modification on A-ring, C-ring and D-ring. And several much potent compounds were studies in vivo to profile their pharmacokinetic properties. Finally, optimization leads to the identification of compound 19a, a potent Hh signaling pathway inhibitor with superior potency in vitro and satisfactory pharmacokinetic properties in vivo. 相似文献
16.
Jian-kang Jiang Xiuli Huang Khalida Shamim Paresma R. Patel Arthur Lee Amy Q. Wang Kimloan Nguyen Gregory Tawa Gregory D. Cuny Paul B. Yu Wei Zheng Xin Xu Philip Sanderson Wenwei Huang 《Bioorganic & medicinal chemistry letters》2018,28(20):3356-3362
The pyrazolo[1,5-a]pyrimidine LDN-193189 is a potent inhibitor of activin receptor-like kinase 2 (ALK2) but is nonselective for highly homologous ALK3 and shows only modest kinome selectivity. Herein, we describe the discovery of a novel series of potent and selective ALK2 inhibitors by replacing the quinolinyl with a 4-(sulfamoyl)naphthyl, yielding ALK2 inhibitors that exhibit not only excellent discrimination versus ALK3 but also high kinome selectivity. In addition, the optimized compound 23 demonstrates good ADME and in vivo pharmacokinetic properties. 相似文献
17.
Yan X Wang Z Sudom A Cardozo M DeGraffenreid M Di Y Fan P He X Jaen JC Labelle M Liu J Ma J McMinn D Miao S Sun D Tang L Tu H Ursu S Walker N Ye Q Powers JP 《Bioorganic & medicinal chemistry letters》2010,20(23):7071-7075
In this communication, human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitory activities of a novel series of diarylsulfones are described. Optimization of this series resulted in several highly potent 11β-HSD1 inhibitors with excellent pharmacokinetic (PK) properties. Compound (S)-25 showed excellent efficacy in a non-human primate ex vivo pharmacodynamic model. 相似文献
18.
Meyers MJ Long SA Pelc MJ Wang JL Bowen SJ Schweitzer BA Wilcox MV McDonald J Smith SE Foltin S Rumsey J Yang YS Walker MC Kamtekar S Beidler D Thorarensen A 《Bioorganic & medicinal chemistry letters》2011,21(21):6545-6553
Fatty acid amide hydrolase (FAAH) is an integral membrane serine hydrolase responsible for the degradation of fatty acid amide signaling molecules such as endocannabinoid anandamide (AEA), which has been shown to possess cannabinoid-like analgesic properties. Herein we report the optimization of spirocyclic 7-azaspiro[3.5]nonane and 1-oxa-8-azaspiro[4.5]decane urea covalent inhibitors of FAAH. Using an iterative design and optimization strategy, lead compounds were identified with a remarkable reduction in molecular weight and favorable CNS drug like properties. 3,4-Dimethylisoxazole and 1-methyltetrazole were identified as superior urea moieties for this inhibitor class. A dual purpose in vivo efficacy and pharmacokinetic screen was designed to be the key decision enabling experiment affording the ability to move quickly from compound synthesis to selection of preclinical candidates. On the basis of the remarkable potency, selectivity, pharmacokinetic properties and in vivo efficacy, PF-04862853 (15p) was advanced as a clinical candidate. 相似文献
19.
The aspartic protease (PR) of the human immunodeficiency virus type 1 (HIV-1) is an important target for the design of specific antiviral agents dedicated to treatment of HIV-1 infection. We have employed computer-assisted combinatorial chemistry methods to design a small focused virtual library of nonsymmetrically substituted cyclic urea inhibitors of the PR. Nonsymmetrical compounds with decreased peptidic character were namely found to inhibit the PR with comparable inhibition potencies as their C2-pseudosymmetric counterparts and to possess superior pharmacokinetic properties. To generate the virtual library of fully nonsymmetrical cyclic urea analogs, diverse reagents were selected from databases of available chemicals with characteristics similar to those of the building blocks of known potent PR inhibitors. The X-ray structure of the protease-inhibitor complex PR-XV-638 was used as the receptor model in the structure-based focusing and in silico screening of the virtual library. A target-specific LUDI-type scoring function, parameterized for a QSAR training set of known cyclic urea inhibitors and validated on a set of compounds not included into the training set, was used to predict the inhibition constants (Ki) of the generated analogs toward the HIV-1 PR. The fragments most frequently occurring in the analogs with the highest predicted inhibition potencies (Ki*<10 pM) were then selected to constitute a highly focused library subset containing novel nonsymmetrical cyclic ureas with predicted Ki*s 1 order of magnitude lower than the most potent known cyclic urea inhibitors. ADME properties calculated for the most promising analogs suggested that the cyclic ureas are endowed with a wide range of favorable pharmacokinetic properties, which may favor the discovery of a potent orally administrable antiviral drug. 相似文献
20.
Jagusch C Negri M Hille UE Hu Q Bartels M Jahn-Hoffmann K Pinto-Bazurco Mendieta MA Rodenwaldt B Müller-Vieira U Schmidt D Lauterbach T Recanatini M Cavalli A Hartmann RW 《Bioorganic & medicinal chemistry》2008,16(4):1992-2010
Novel chemical entities were prepared via Suzuki and S(N) reaction as AC-ring substrate mimetics of CYP17. The synthesised compounds 1-31 were tested for activity using human CYP17 expressed in Escherichia coli. Promising compounds were tested for selectivity against hepatic CYP enzymes (3A4, 2D6, 1A2, 2C9, 2C19, 2B6). Two potent inhibitors (27, IC50 = 373 nM/28, IC50 = 953 nM) were further examined in rats regarding their effects on plasma testosterone levels and their pharmacokinetic properties. Compound 28 was similarly active as abiraterone and showed better pharmacokinetic properties (higher bioavailability, t(1/2) 9.5 h vs 1.6 h). Docking studies revealed two new binding modes different from the one of the substrates and steroidal inhibitors. 相似文献