共查询到20条相似文献,搜索用时 15 毫秒
1.
Bernd Buettelmann Theresa M. Ballard Rodolfo Gasser Holger Fischer Maria-Clemencia Hernandez Frédéric Knoflach Henner Knust Heinz Stadler Andrew W. Thomas Gerhard Trube 《Bioorganic & medicinal chemistry letters》2009,19(20):5958-5961
In a search for GABAA α5 ligands that combine high subtype binding selectivity with a marked inverse agonism imidazo[1,5-a][1,2,4]-triazolo[1,5-d][1,4]benzodiazepines were identified as a promising class. A short tandem reaction allowed rapid access to this chemical series, thereby facilitating rapid SAR generation which guided the optimization process. Two compounds (10e and 11f) were found to be active in an in vivo paradigm for cognitive improvement. 相似文献
2.
《Bioorganic & medicinal chemistry letters》2020,30(22):127536
The identification and SAR development of a series of negative allosteric modulators of the GABAA α5 receptor is described. This novel series of compounds was optimised to provide analogues with high GABAA α5 binding affinity, high α5 negative allosteric modulatory activity, good functional subtype selectivity and low microsomal turnover, culminating in identification of ONO-8590580. 相似文献
3.
Nadim S. Shaikh Jitesh P. Iyer Yogesh S. Munot Partha P. Mukhopadhyay Amol A. Raje Ranganayaki Nagaraj Vijay Jamdar Ravindra Gavhane Mahendra Lohote Prasad Sherkar Madhu Bala Rajkanth Petla Ashwinkumar Meru Dhananjay Umrani Sreekanth Rouduri Sachin Joshi Satyanarayan Reddy Vishwottam Kandikere Kasim A. Mookhtiar 《Bioorganic & medicinal chemistry letters》2019,29(16):2208-2217
Targeting nuclear receptor RORγ is recognized to be beneficial in multiple autoimmune disorders. We disclosed new indole analogues as potent RORγ inverse agonists. RO-2 as one of the potent and orally bioavailable compounds was evaluated in various models of autoimmune disorder. It showed potent suppression of downstream markers of RORγt activity in murine and human primary cells, ex vivo PD assay and in multiple animal models of autoimmune diseases. The results indicate the potential of these indole analogues as orally bioavailable small molecule inverse agonists of RORγt, efficacious in various Th17 driven models of autoimmune disorders. 相似文献
4.
Jérôme Amaudrut Maria A. Argiriadi Martine Barth Eric C. Breinlinger Didier Bressac Pierre Broqua David J. Calderwood Mohamed Chatar Kevin P. Cusack Stephen B. Gauld Sébastien Jacquet Rajesh V. Kamath Michael E. Kort Valérie Lepais Jean-Michel Luccarini Philippe Masson Christian Montalbetti Laurent Mounier Craig D. Wallace 《Bioorganic & medicinal chemistry letters》2019,29(14):1799-1806
A high-throughput screen against Inventiva’s compound library using a Gal4/RORγ-LBD luciferase reporter gene assay led to the discovery of a new series of quinoline sulphonamides as RORγ inhibitors, eventually giving rise to a lead compound having an interesting in vivo profile after oral administration. This lead was evaluated in a target engagement model in mouse, where it reduced IL-17 cytokine production after immune challenge. It also proved to be active in a multiple sclerosis model (EAE) where it reduced the disease score. The synthesis, structure activity relationship (SAR) and biological activity of these derivatives is described herein. 相似文献
5.
Luckhurst CA Stein LA Furber M Webb N Ratcliffe MJ Allenby G Botterell S Tomlinson W Martin B Walding A 《Bioorganic & medicinal chemistry letters》2011,21(1):492-496
Small molecule isoindoline and tetrahydroisoquinoline derivatives have been identified as selective agonists of human peroxisome proliferator-activated receptor δ (PPARδ. Compound 18 demonstrated efficacy in a biomarker for increased fatty acid oxidation, with upregulation of pyruvate dehydrogenase kinase, isozyme 4 (PDK4) in human primary myotubes. 相似文献
6.
Isaac E. Marx Erin F. DiMauro Alan Cheng Renee Emkey Stephen A. Hitchcock Liyue Huang Ming Y. Huang Jason Human Josie H. Lee Xingwen Li Matthew W. Martin Ryan D. White Robert T. Fremeau Vinod F. Patel 《Bioorganic & medicinal chemistry letters》2009,19(1):31-35
A series of α-amidosulfones were found to be potent and selective agonists of CB2. The discovery, synthesis, and structure–activity relationships of this series of agonists are reported. In addition, the pharmacokinetic properties of the most promising compounds are profiled. 相似文献
7.
Morriello GJ Wendt HR Bansal A Di Salvo J Feighner S He J Hurley AL Hreniuk DL Salituro GM Reddy MV Galloway SM McGettigan KK Laws G McKnight C Doss GA Tsou NN Black RM Morris J Ball RG Sanfiz AT Streckfuss E Struthers M Edmondson SD 《Bioorganic & medicinal chemistry letters》2011,21(6):1865-1870
A novel class of human β3-adrenergic receptor agonists was designed in effort to improve selectivity and metabolic stability versus previous disclosed β3-AR agonists. As observed, many of the β3-AR agonists seem to need the acyclic ethanolamine core for agonist activity. We have synthesized derivatives that constrained this moiety by introduction of a pyrrolidine. This unique modification maintains human β3 functional potency with improved selectivity versus ancillary targets and also eliminates the possibility of the same oxidative metabolites formed from cleavage of the N-C bond of the ethanolamine. Compound 39 exhibited excellent functional β3 agonist potency across species with good pharmacokinetic properties in rat, dog, and rhesus monkeys. Early de-risking of this novel pyrrolidine core (44) via full AMES study supports further research into various new β3-AR agonists containing the pyrrolidine moiety. 相似文献
8.
Lee R. Roberts Paul V. Fish R. Ian Storer Gavin A. Whitlock 《Bioorganic & medicinal chemistry letters》2009,19(11):3113-3117
Novel pyrroloimidazoles have been identified as potent partial agonists of the α1A adrenergic receptor, with good selectivity over the α1B, α1D and α2A receptor subtypes. Pyrimidine 19 possessed attractive CNS drug-like properties with good membrane permeability and no evidence for P-gp mediated efflux. 相似文献
9.
Guido Achermann Theresa M. Ballard Francesca Blasco Pierre-Emmanuel Broutin Bernd Büttelmann Holger Fischer Martin Graf Maria-Clemencia Hernandez Peter Hilty Frédéric Knoflach Andreas Koblet Henner Knust Anke Kurt James R. Martin Raffaello Masciadri Richard H.P. Porter Heinz Stadler Andrew W. Thomas Gerhard Trube Jürgen Wichmann 《Bioorganic & medicinal chemistry letters》2009,19(19):5746-5752
Through iterative design cycles we have discovered a number of novel new classes where the imidazo[1,5-a][1,2,4]-triazolo[1,5-d][1,4]benzodiazepine was deemed the most promising GABAA α5 inverse agonist class with potential for cognitive enhancement. This class combines a modest subtype binding selectivity with inverse agonism and has the most favourable molecular properties for further lead optimisation towards a central nervous system (CNS) acting medicine. 相似文献
10.
Albert Enz Dominik Feuerbach Mathias U. Frederiksen Conrad Gentsch Konstanze Hurth Werner Müller Joachim Nozulak Bernard L. Roy 《Bioorganic & medicinal chemistry letters》2009,19(5):1287-1291
A novel class of α7 nicotinic acetylcholine receptor (nAChR) agonists has been discovered through high-throughput screening. The cis γ-lactam scaffold has been optimized to reveal highly potent and selective α7 nAChR agonists with in vitro activity and selectivity and with good brain penetration in mice. 相似文献
11.
Aurélie Hurtevent Morgan Le Naour Veronique Leclerc Pascal Carato Patricia Melnyk Nathalie Hennuyer 《Journal of enzyme inhibition and medicinal chemistry》2013,28(1):524-538
Abstract A series of nitrogen heterocycles containing α–ethoxyphenylpropionic acid derivatives were designed as dual PPARα/γ agonist ligands for the treatment of type 2 diabetes (T2D) and its complications. 6-Benzoyl-benzothiazol-2-one was the most tolerant of the tested heterocycles in which incorporation of O-methyl oxime ether and trifluoroethoxy group followed by enantiomeric resolution led to the (S)-stereoisomer 44?b displaying the best in vitro pharmacological profile. Compound 44?b acted as a very potent full PPARγ agonist and a weak partial agonist on the PPARα receptor subtype. Compound 44?b showed high efficacy in an ob/ob mice model with significant decreases in serum triglyceride, glucose and insulin levels but mostly with limited body-weight gain and could be considered as a selective PPARγ modulator (SPPARγM). 相似文献
12.
Hudkins RL Aimone LD Bailey TR Bendesky RJ Dandu RR Dunn D Gruner JA Josef KA Lin YG Lyons J Marcy VR Mathiasen JR Sundar BG Tao M Zulli AL Raddatz R Bacon ER 《Bioorganic & medicinal chemistry letters》2011,21(18):5493-5497
H(3)R structure-activity relationships on a novel class of pyridazin-3-one H(3)R antagonists/inverse agonists are disclosed. Modifications of the pyridazinone core, central phenyl ring and linker led to the identification of molecules with excellent target potency, selectivity and pharmacokinetic properties. Compounds 13 and 21 displayed potent functional H(3)R antagonism in vivo in the rat dipsogenia model and demonstrated robust wake activity in the rat EEG/EMG model. 相似文献
13.
Nan Zhang Semiramis Ayral-Kaloustian James T. Anderson Thai Nguyen Sasmita Das Aranapakam M. Venkatesan Natasja Brooijmans Judy Lucas Ker Yu Irwin Hollander Robert Mallon 《Bioorganic & medicinal chemistry letters》2010,20(12):3526-3529
A series of 5-ureidobenzofuran-3-one indoles as potent inhibitors of PI3Kα and mTOR has been developed. The best potency in cells was obtained when the urea group was extended to a 4-[2-(dimethylamino)ethyl]methylamino amidophenyl group. A 7-fluoro group on the indole ring also enhanced cellular potency. Compound 18i, incorporating the optimal functional groups, showed high potency in cellular lines and was further studied in vivo. It was able to inhibit the biomarker phosphorylation for 8 h when dosed at 25 mg/kg iv. In the MDA-MB-361 breast cancer model, it shrank the tumor size remarkably when dosed at 25 mg/kg iv on days 1, 5, and 9. 相似文献
14.
Liang G Aldous S Merriman G Levell J Pribish J Cairns J Chen X Maignan S Mathieu M Tsay J Sides K Rebello S Whitely B Morize I Pauls HW 《Bioorganic & medicinal chemistry letters》2012,22(2):1049-1054
A solid phase combinatorial library was designed based on X-ray structures and in-silico models to explore an inducible S4+ pocket, which is formed by a simple side-chain rotation of Tyr95. This inducible S4+ pocket is unique to β-tryptase and does not exist for other trypsin-like serine proteases of interest. Therefore, inhibitors utilizing this pocket have inherent advantages for being selective against other proteases in the same family. A member of this library was found to be a potent and selective β-tryptase inhibitor with a suitable pharmacokinetic profile for further clinical evaluation. 相似文献
15.
Tatsuya Maruyama Kenichi Onda Masahiko Hayakawa Norio Seki Takumi Takahashi Hiroyuki Moritomo Takayuki Suzuki Tetsuo Matsui Toshiyuki Takasu Itsuro Nagase Mitsuaki Ohta 《Bioorganic & medicinal chemistry》2009,17(9):3283-3294
In the search for potent and selective human β3-adrenergic receptor (AR) agonists as potential drugs for the treatment of obesity and noninsulin-dependent (type II) diabetes, a novel series of phenoxypropanolamine derivatives containing acetanilides were prepared and their biological activities were evaluated at the human β3-, β2-, and β1-ARs. Several of the analogues (21a, 21b, and 27a) exhibited potent agonistic activity at the β3-AR. Among the compounds described herein, the N-methyl-1-benzylimidazol-2-ylacetanilide derivative (21b) was found to be the most potent and selective β3-AR agonist, with an EC50 value of 0.28 μM and no agonistic activity for either the β1- or β2-AR. In addition, 21b showed significant hypoglycemic activity in a rodent diabetic model. 相似文献
16.
Kuldeep K. Roy Santoshkumar Tota Tusha Tripathi Subhash Chander Chandishwar Nath Anil K. Saxena 《Bioorganic & medicinal chemistry》2012,20(21):6313-6320
The optimization of our previous lead compound 1 (AChE IC50 = 3.31 μM) through synthesis and pharmacology of a series of novel carbamates is reported. The synthesized compounds were evaluated against mouse brain AChE enzyme using the colorimetric method described by Ellman et al. The three compounds 6a (IC50 = 2.57 μM), 6b (IC50 = 0.70 μM) and 6i (IC50 = 2.56 μM) exhibited potent in vitro AChE inhibitory activities comparable to the drug rivastigmine (IC50 = 1.11 μM). Among them, the compound 6b has been selected as possible optimized lead for further neuropharmacological studies. In addition, the AChE–carbamate Michaelis complexes of these potent compounds including rivastigmine and ganstigmine have been modeled using covalent docking protocol of GOLD and important direct/indirect interactions contributing to stabilization of the AChE–carbamate Michaelis complexes have been investigated. 相似文献
17.
Jacobsen JR Choi SK Combs J Fournier EJ Klein U Pfeiffer JW Thomas GR Yu C Moran EJ 《Bioorganic & medicinal chemistry letters》2012,22(2):1213-1218
A multivalent approach was applied to the design of long-acting inhaled β(2)-adrenoceptor agonists. A series of dimeric arylethanolamines based on the short acting β(2)-adrenoceptor agonist albuterol were prepared, varying the nature and length of the linker between the basic nitrogens. None of the C(2)-symmetric dimers demonstrated increased potency, however dimer 5j, derived from 4-phenethylamine, was found to have increased binding potency in vitro relative to the parent monomer. Optimization of this structure led to the identification of 22 (milveterol) which demonstrates high potency in vitro and long duration of action in a guinea pig model of bronchoprotection. 相似文献
18.
Won Jun Choi Hyuk Woo Lee Hea Ok Kim Moshe Chinn Zhan-Guo Gao Amit Patel Kenneth A. Jacobson Hyung Ryong Moon Young Hoon Jung Lak Shin Jeong 《Bioorganic & medicinal chemistry》2009,17(23):8003-8011
On the basis of a bioisosteric rationale, 4′-thionucleoside analogues of IB-MECA (N6-(3-Iodo-benzyl)-9-(5′-methylaminocarbonyl-β-d-ribofuranosyl)adenine), which is a potent and selective A3 adenosine receptor (AR) agonist, were synthesized from d-gulonic acid γ-lactone. The 4′-thio analogue (5h) of IB-MECA showed extremely high binding affinity (Ki = 0.25 nM) at the human A3AR and was more potent than IB-MECA (Ki = 1.4 nM). Bulky substituents at the 5′-uronamide position, such as cyclohexyl and 2-methylbenzyl, in this series of 2-H nucleoside derivatives were tolerated in A3AR binding, although small alkyl analogues were more potent. 相似文献
19.
Paul A. Barsanti Weibo Wang Zhi-Jie Ni David Duhl Nathan Brammeier Eric Martin Dirksen Bussiere Annette O. Walter 《Bioorganic & medicinal chemistry letters》2010,20(1):157-160
A series of tetrahydro-β-carbolines were identified by HTS as inhibitors of the kinesin Eg5. Molecular modeling and medicinal chemistry techniques were employed to explore the SAR for this series with a focus of removing potential metabolic liabilities and improving cellular potency. 相似文献
20.
Etienne Thoreau Jean-Marie Arlabosse Claire Bouix-Peter Sandrine Chambon Laurent Chantalat Sébastien Daver Laurence Dumais Gwenaëlle Duvert Angélique Feret Gilles Ouvry Jonathan Pascau Catherine Raffin Nicolas Rodeville Catherine Soulet Samuel Tabet Sandrine Talano Thibaud Portal 《Bioorganic & medicinal chemistry letters》2018,28(10):1736-1741
Retinoids have a dominant role in topical acne therapy and to date, only RARβ and RARγ dual agonists have reached the market. Given the tissue distribution of RAR isoforms, it was hypothesized that developing RARγ -selective agonists could yield a new generation of topical acne treatments that would increase safety margins while maintaining the robust efficacy of previous drugs. Structural knowledge derived from the X-ray structure of known γ-selective CD437, suggested the design of a novel triaryl series of agonists which was optimized and ultimately led to the discovery of Trifarotene/CD5789. 相似文献