共查询到20条相似文献,搜索用时 15 毫秒
1.
Marlys Hammond David G. Washburn Tram H. Hoang Sharada Manns James S. Frazee Hiroko Nakamura Jaclyn R. Patterson Walter Trizna Charlene Wu Leonard M. Azzarano Rakesh Nagilla Melanie Nord Rebecca Trejo Martha S. Head Baoguang Zhao Angela M. Smallwood Kendra Hightower Nicholas J. Laping Christine G. Schnackenberg Scott K. Thompson 《Bioorganic & medicinal chemistry letters》2009,19(15):4441-4445
The lead serum and glucocorticoid-related kinase 1 (SGK1) inhibitors 4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid (1) and {4-[5-(2-naphthalenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]phenyl}acetic acid (2) suffer from low DNAUC values in rat, due in part to formation and excretion of glucuronic acid conjugates. These PK/glucuronidation issues were addressed either by incorporating a substituent on the 3-phenyl ring ortho to the key carboxylate functionality of 1 or by substituting on the group in between the carboxylate and phenyl ring of 2. Three of these analogs have been identified as having good SGK1 inhibition potency and have DNAUC values suitable for in vivo testing. 相似文献
2.
Dmitry O. Koltun Timur M. Zilbershtein Vasily A. Migulin Natalya I. Vasilevich Eric Q. Parkhill Andrei I. Glushkov Malcolm J. McGregor Sandra A. Brunn Nancy Chu Jia Hao Nevena Mollova Kwan Leung Jeffrey W. Chisholm Jeff Zablocki 《Bioorganic & medicinal chemistry letters》2009,19(15):4070-4074
Two structurally distinct series of SCD (Δ9 desaturase) inhibitors (1 and 2) have been previously reported by our group. In the present work, we merged the structural features of the two series. This led to the discovery of compound 5b (CVT-12,012) which is highly potent in a human cell-based (HEPG2) SCD assay (IC50 = 6 nM). This compound has 78% oral bioavailability in rats and is preferentially distributed into liver (76 times vs plasma) with relatively low brain penetration. In a five-day study (sucrose fed rats) compound 5b significantly reduced SCD activity in a dose-dependent manner as determined by GC analysis of fatty acid composition in plasma and liver, and significantly reduced liver triglycerides versus the control group (~50%). 相似文献
3.
Patel D Jain M Shah SR Bahekar R Jadav P Joharapurkar A Dhanesha N Shaikh M Sairam KV Kapadnis P 《Bioorganic & medicinal chemistry letters》2012,22(2):1111-1117
A novel series of pTyr mimetics containing triaryl-sulfonamide derivatives (5a-r) are reported as potent and selective PTP1B inhibitors. Some of the test compounds (5o and 5p) showed excellent selectivity towards PTP1B over various PTPs, including TCPTP (in vitro). The lead compound 5o showed potent antidiabetic activity (in vivo), along with improved pharmacokinetic profile. These preliminary results confirm discovery of highly potent and selective PTP1B inhibitors for the treatment of T2DM. 相似文献
4.
Theodore C. Jessop James E. Tarver Marianne Carlsen Amy Xu Jason P. Healy Alexander Heim-Riether Qinghong Fu Jerry A. Taylor David J. Augeri Min Shen Terry R. Stouch Ronald V. Swanson Leslie W. Tari Michael Hunter Isaac Hoffman Philip E. Keyes Xuan-Chuan Yu Maricar Miranda Qingyun Liu Jonathan C. Swaffield Kenneth G. Carson 《Bioorganic & medicinal chemistry letters》2009,19(23):6784-6787
A series of deoxycytidine kinase inhibitors was simultaneously optimized for potency and PK properties. A co-crystal structure then allowed merging this series with a high throughput screening hit to afford a highly potent, selective and orally bioavailable inhibitor, compound 10. This compound showed dose dependent inhibition of deoxycytidine kinase in vivo. 相似文献
5.
Matthew G. Bursavich David Dastrup Mark Shenderovich Kraig M. Yager Daniel M. Cimbora Brandi Williams D. Vijay Kumar 《Bioorganic & medicinal chemistry letters》2013,23(24):6829-6833
Mps1, also known as TTK, is a mitotic checkpoint protein kinase that has become a promising new target of cancer research. In an effort to improve the lead-likeness of our recent Mps1 purine lead compounds, a scaffold hopping exercise has been undertaken. Structure-based design, principles of conformational restriction, and subsequent scaffold hopping has led to novel pyrrolopyrimidine and quinazoline Mps1 inhibitors. These new single-digit nanomolar leads provide the basis for developing potent, novel Mps1 inhibitors with improved drug-like properties. 相似文献
6.
Christopher W. West Marc Adler Danny Arnaiz Deborah Chen Kieu Chu Giovanna Gualtieri Elena Ho Christoph Huwe David Light Gary Phillips Rebecca Pulk Drew Sukovich Marc Whitlow Shendong Yuan Judi Bryant 《Bioorganic & medicinal chemistry letters》2009,19(19):5712-5715
In this Letter we report the synthesis and evaluation of a series of non-amidine inhibitors of Urokinase Plasminogen Activator (uPA). Starting from compound 1, a significant change provided compounds in which the amidine, binding in the S1 pocket, was replaced with a primary amine. Further modifications led to the identification of potent, selective, and orally bioavailable uPA inhibitors. 相似文献
7.
Zhenrong Xu Salvacion Cacatian Jing Yuan Robert D. Simpson Lanqi Jia Wei Zhao Colin M. Tice Patrick T. Flaherty Joan Guo Alexey Ishchenko Suresh B. Singh Zhongren Wu Brian M. McKeever Boyd B. Scott Yuri Bukhtiyarov Jennifer Berbaum Jennifer Mason Reshma Panemangalore Maria Grazia Cappiello Ross Bentley David A. Claremon 《Bioorganic & medicinal chemistry letters》2010,20(2):694-699
Structure-guided drug design led to new alkylamine renin inhibitors with improved in vitro and in vivo potency. Lead compound 21a, has an IC50 of 0.83 nM for the inhibition of human renin in plasma (PRA). Oral administration of 21a at 10 mg/kg resulted in >20 h reduction of blood pressure in a double transgenic rat model of hypertension. 相似文献
8.
Barrett DG Catalano JG Deaton DN Long ST McFadyen RB Miller AB Miller LR Samano V Tavares FX Wells-Knecht KJ Wright LL Zhou HQ 《Bioorganic & medicinal chemistry letters》2007,17(1):22-27
Starting from a potent ketone-based inhibitor with poor drug properties, incorporation of P(2)-P(3) elements from a ketoamide-based inhibitor led to the identification of a hybrid series of ketone-based cathepsin K inhibitors with better oral bioavailability than the starting ketone. 相似文献
9.
J B Rewinkel H Lucas M J Smit A B Noach T G van Dinther A M Rood A J Jenneboer C A van Boeckel 《Bioorganic & medicinal chemistry letters》1999,9(19):2837-2842
Replacement of the highly basic benzamidine moiety with moderate basic amino-bicycloaryl moieties in a series of thrombin inhibitors related to NAPAMP provided potent enzyme inhibition and significant improvements in membrane transport and oral bioavailability. 相似文献
10.
Joanne L. Thomson Wesley P. Blackaby Andrew S.R. Jennings Simon C. Goodacre Andrew Pike Steve Thomas Terry A. Brown Alison Smith Gopalan Pillai Leslie J. Street Richard T. Lewis 《Bioorganic & medicinal chemistry letters》2009,19(8):2235-2239
A series of heterocyclic sulfonamides have been developed which are potent and selective inhibitors of hGlyT1. SAR studies to optimise the in vitro and in vivo properties are described. Optimisation of the central scaffold resulted in cyclohexane sulfones 28 and 29, which have good PK properties and show promise for further development. 相似文献
11.
Potent and orally bioavailable noncysteine-containing inhibitors of protein farnesyltransferase. 总被引:1,自引:0,他引:1
D J Augeri D Janowick D Kalvin G Sullivan J Larsen D Dickman H Ding J Cohen J Lee R Warner P Kovar S Cherian B Saeed H Zhang S Tahir S C Ng H Sham S H Rosenberg 《Bioorganic & medicinal chemistry letters》1999,9(8):1069-1074
Potent and orally bioavailable nonthiol-containing inhibitors of protein farnesyltransferase are described. Oral bioavailability was achieved by replacement of the pyridyl ether moiety of 1 with a 2-substituted furan ether to give 4. Potency was regained with 2,5-disubstituted furan ethers while maintaining the bioavailability inherent in 4. p-Chlorophenylfuran ether 24 is 0.7 nM in vitro (FTase) and is 32% bioavailable in the mouse, 30% bioavailable in rats, and 21% bioavailable in dogs. 相似文献
12.
Shyh-Ming Yang Yuting Tang Rui Zhang Huajun Lu Gee-Hong Kuo Michael D. Gaul Yaxin Li George Ho James G. Conway Yin Liang James M. Lenhard Keith T. Demarest William V. Murray 《Bioorganic & medicinal chemistry letters》2013,23(24):6773-6776
A new series of urea-based, 4-bicyclic heteroaryl-piperidine derivatives as potent SCD1 inhibitors is described. The structure–activity relationships focused on bicyclic heteroarenes and aminothiazole–urea portions are discussed. A trend of dose-dependent decrease in body weight gain in diet-induced obese (DIO) mice is also demonstrated. 相似文献
13.
John S. Debenham Thomas H. Graham Andreas Verras Yong Zhang Matthew J. Clements Jeffrey T. Kuethe Christina Madsen-Duggan Wensheng Liu Urmi R. Bhatt Dunlu Chen Qing Chen Margarita Garcia-Calvo Wayne M. Geissler Huaibing He Xiaohua Li JeanMarie Lisnock Zhu Shen Xinchun Tong Dong-Ming Shen 《Bioorganic & medicinal chemistry letters》2013,23(23):6228-6233
The synthesis, SAR, binding affinities and pharmacokinetic profiles are described for a series of cyclohexane-based prolylcarboxypeptidase (PrCP) inhibitors discovered by high throughput screening. Compounds show high levels of ex vivo target engagement in mouse plasma 20 h post oral dose. 相似文献
14.
《Bioorganic & medicinal chemistry letters》2014,24(5):1437-1441
Design, synthesis, and biological evaluation of pyridazine-based, 4-bicyclic heteroaryl-piperidine derivatives as potent stearoyl-CoA desaturase-1 (SCD1) inhibitors are described. In a chronic study of selected analog (3e) in Zucker fa/fa (ZF) rat, dose-dependent decrease of body weight gain and plasma fatty acid desaturation index (DI) in both C16 and C18 are also demonstrated. The results indicate that the plasma fatty acid DI may serve as an indicator for direct target engagement and biomarker for SCD1 inhibition. 相似文献
15.
Matthew A.J. Duncton Eugene L. Piatnitski Chekler Reeti Katoch-Rouse Dan Sherman Wai C. Wong Leon M. Smith Joel K. Kawakami Alexander S. Kiselyov Daniel L. Milligan Chris Balagtas Yaron R. Hadari Ying Wang Sheetal N. Patel Robin L. Rolster James R. Tonra David Surguladze Stan Mitelman Paul Kussie Peter Bohlen Jacqueline F. Doody 《Bioorganic & medicinal chemistry》2009,17(2):731-740
A series of arylphthalazine derivatives were synthesized and evaluated as antagonists of VEGF receptor II (VEGFR-2). IM-094482 57, which was prepared in two steps from commercially available starting materials, was found to be a potent inhibitor of VEGFR-2 in enzymatic, cellular and mitogenic assays (comparable activity to ZD-6474). Additionally, 57 inhibited the related receptor, VEGF receptor I (VEGFR-1), and showed excellent exposure when dosed orally to female CD-1 mice. 相似文献
16.
Genicot C Christophe B Collart P Gillard M Goossens L Hénichart JP Lassoie MA Moureau F Neuwels M Nicolas JM Pasau P Quéré L Ryckmans T Stiernet F Taverne T Van Keulen BJ 《Bioorganic & medicinal chemistry letters》2003,13(3):437-442
Benzyloxyphenethylpiperazines are a new class of high affinity NK1 receptor antagonists. Oral bioavailability and selectivity can be fine tuned by the nature of the substituents on the basic nitrogen atom. Addition of substituents with a carboxylic acid group led to very selective and orally active NK1 antagonists free of interaction with L-type calcium channels. 相似文献
17.
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
18.
Coburn CA Rush DM Williams PD Homnick C Lyle EA Lewis SD Lucas BJ Di Muzio-Mower JM Juliano M Krueger JA Vastag K Chen IW Vacca JP 《Bioorganic & medicinal chemistry letters》2000,10(10):1069-1072
A new class of conformationally constrained thrombin inhibitors is described. These compounds contain a unique bicyclic pyridone scaffold which serves as a P3P2 dipeptide surrogate. The synthesis and antithrombotic activity of these inhibitors is reported. 相似文献
19.
Levell J Astles P Eastwood P Cairns J Houille O Aldous S Merriman G Whiteley B Pribish J Czekaj M Liang G Maignan S Guilloteau JP Dupuy A Davidson J Harrison T Morley A Watson S Fenton G McCarthy C Romano J Mathew R Engers D Gardyan M Sides K Kwong J Tsay J Rebello S Shen L Wang J Luo Y Giardino O Lim HK Smith K Pauls H 《Bioorganic & medicinal chemistry》2005,13(8):2859-2872
Tryptase is a serine protease found almost exclusively in mast cells. It has trypsin-like specificity, favoring cleavage of substrates with an arginine (or lysine) at the P1 position, and has optimal catalytic activity at neutral pH. Current evidence suggests tryptase beta is the most important form released during mast cell activation in allergic diseases. It is shown to have numerous pro-inflammatory cellular activities in vitro, and in animal models tryptase provokes broncho-constriction and induces a cellular inflammatory infiltrate characteristic of human asthma. Screening of in-house inhibitors of factor Xa (a closely related serine protease) identified beta-amidoester benzamidines as potent inhibitors of recombinant human betaII tryptase. X-ray structure driven template modification and exchange of the benzamidine to optimize potency and pharmacokinetic properties gave selective, potent and orally bioavailable 4-(3-aminomethyl phenyl)piperidinyl-1-amides. 相似文献
20.
Zbinden KG Obst-Sander U Hilpert K Kühne H Banner DW Böhm HJ Stahl M Ackermann J Alig L Weber L Wessel HP Riederer MA Tschopp TB Lavé T 《Bioorganic & medicinal chemistry letters》2005,15(23):5344-5352
We describe the structure-based design and synthesis of highly potent, orally bioavailable tissue factor/factor VIIa inhibitors which interfere with the coagulation cascade by selective inhibition of the extrinsic pathway. 相似文献