共查询到20条相似文献,搜索用时 78 毫秒
1.
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
2.
Manley PJ Zartman A Paone DV Burgey CS Henze DA Della Penna K Desai R Leitl MD Lemaire W White RB Yeh S Urban MO Kane SA Hartman GD Bilodeau MT Trotter BW 《Bioorganic & medicinal chemistry letters》2011,21(8):2359-2364
A novel series of decahydroquinoline CB2 agonists is described. Optimization of the amide substituent led to improvements in CB2/CB1 selectivity as well as physical properties. Two key compounds were examined in the rat CFA model of acute inflammatory pain. A moderately selective CB2 agonist was active in this model. A CB2 agonist lacking functional CB1 activity was inactive in this model despite high in vivo exposure both peripherally and centrally. 相似文献
3.
David G. Washburn Tram H. Hoang James S. Frazee Latisha Johnson Marlys Hammond Sharada Manns Kevin P. Madauss Shawn P. Williams Chaya Duraiswami Thuy B. Tran Eugene L. Stewart Eugene T. Grygielko Lindsay E. Glace Walter Trizna Rakesh Nagilla Jeffrey D. Bray Scott K. Thompson 《Bioorganic & medicinal chemistry letters》2009,19(16):4664-4668
We have designed and synthesized a novel series of pyrrolidinones as progesterone receptor partial agonists. Compounds from this series had improved AR selectivity, rat pharmacokinetic properties, and in vivo potency compared to the lead compound. In addition, these compounds had improved selectivity against hERG channel inhibition. 相似文献
4.
I Kers I Macsari G Csjernyik M Nylöf K Skogholm L Sandberg A Minidis T Bueters J Malmborg AB Eriksson PE Lund E Venyike L Luo JE Nyström Y Besidski 《Bioorganic & medicinal chemistry letters》2012,22(19):6108-6115
The Na(V)1.7 ion channel is an attractive target for development of potential analgesic drugs based on strong genetic links between mutations in the gene coding for the channel protein and inheritable pain conditions. The (S)-N-chroman-3-ylcarboxamide series, exemplified by 1, was used as a starting point for development of new channel blockers, resulting in the phenethyl nicotinamide series. The structure and activity relationship for this series was established and the metabolic issues of early analogues were addressed by appropriate substitutions. Compound 33 displayed acceptable overall in vitro properties and in vivo rat PK profile. 相似文献
5.
McKerrecher D Allen JV Caulkett PW Donald CS Fenwick ML Grange E Johnson KM Johnstone C Jones CD Pike KG Rayner JW Walker RP 《Bioorganic & medicinal chemistry letters》2006,16(10):2705-2709
The optimisation of a series of glucokinase activators is described, including attempts to uncouple the relationship between potency and plasma protein binding, and to better understand the key pharmacokinetic properties of the series. The use of unbound clearance as an optimisation parameter facilitated the identification of GKA50, a compound which combines excellent potency and pharmacokinetics with good free drug levels and solubility, and exhibits in vivo efficacy at 1mg/kg po in an acute rat OGTT model. 相似文献
6.
Guillaume Duvey Benjamin Perry Emmanuel Le Poul Sonia Poli Beatrice Bonnet Nathalie Lambeng Delphine Charvin Tansy Donovan-Rodrigues Hasnaà Haddouk Stefania Gagliardi Jean-Philippe Rocher 《Bioorganic & medicinal chemistry letters》2013,23(16):4523-4527
A series of potent non-acetylinic negative allosteric modulators of the metabotropic glutamate receptor 5 (mGlu5 NAMs) was developed starting from HTS screening hit 1. Potency was improved via iterative SAR, and physicochemical properties were optimized to deliver orally bioavailable compounds acceptable for in vivo testing. A lead molecule from the series demonstrated dose-dependent activity in the second phase of the rat formalin test from 30 mg/kg, and a preliminary PK/PD relationship was established. 相似文献
7.
Trotter BW Nanda KK Burgey CS Potteiger CM Deng JZ Green AI Hartnett JC Kett NR Wu Z Henze DA Della Penna K Desai R Leitl MD Lemaire W White RB Yeh S Urban MO Kane SA Hartman GD Bilodeau MT 《Bioorganic & medicinal chemistry letters》2011,21(8):2354-2358
A new series of imidazopyridine CB2 agonists is described. Structural optimization improved CB2/CB1 selectivity in this series and conferred physical properties that facilitated high in vivo exposure, both centrally and peripherally. Administration of a highly selective CB2 agonist in a rat model of analgesia was ineffective despite substantial CNS exposure, while administration of a moderately selective CB2/CB1 agonist exhibited significant analgesic effects. 相似文献
8.
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
9.
Win 49596 is an orally active antiandrogen in the rat. This report describes a series of in vitro and in vivo studies which were performed to characterize the mechanism of action of this compound. In vitro competition and Lineweaver-Burk analyses indicate that Win 49596 binds competitively to the rat ventral prostate androgen receptor with a Ki of 2.2 +/- 0.4 microM. Similar to other androgen antagonists, the relative binding affinity (RBA) of Win 49596 was greater after 1 h of incubation with androgen receptor than after an 18 h incubation (RBA of 2.2 versus 0.05, respectively). Win 49596 did not bind to rat cytosolic uterine estrogen or progesterone receptors or thymus glucocorticoid receptors. Furthermore, Win 49596 did not inhibit rat ventral prostate 5 alpha-reductase or 3 alpha-oxidoreductase, rat adrenal 3 beta-hydroxysteroid dehydrogenase or human placental aromatase activity in vitro at concentrations as high as 10 microM. A series of in vivo studies demonstrated that Win 49596 inhibited the uptake of [3H]testosterone as well as testosterone-induced nuclear accumulation of androgen receptor in the rat ventral prostate. Collectively, these results support direct androgen receptor antagonism as the mechanism for the antiandrogenic effects of Win 49596. 相似文献
10.
Paul M. Wehn Paul E. Harrington Timothy J. Carlson James Davis Pierre Deprez Christopher H. Fotsch Mark P. Grillo Jenny Ying-Lin Lu Sean Morony Kanaka Pattabiraman Steve F. Poon Jeff D. Reagan David J. St. Jean Taoues Temal Minghan Wang Yuhua Yang Charles Henley Sarah E. Lively 《Bioorganic & medicinal chemistry letters》2013,23(24):6625-6628
A series of urea based calcimimetics was optimized for potency and oral bioavailability. Crucial to this process was overcoming the poor pharmacokinetic properties of lead thiazole 1. Metabolism-guided modifications, characterized by the use of metabolite identification (ID) and measurement of time dependent inhibition (TDI) of CYP3A4, were essential to finding a compound suitable for oral dosing. Calcimimetic 18 exhibited excellent in vivo potency in a 5/6 nephrectomized rat model and cross-species pharmacokinetics. 相似文献
11.
Hong-Ju Y He L Wei-Guo S Nan Z Wei-Xiu Y Zhong-Wei J Jun-Wei W Zheng-Hua G Bo-Hua Z Zhi-Pu L Zhe-Hui G 《Bioorganic & medicinal chemistry letters》2004,14(10):2537-2541
A series of mutual prodrugs derived from gabapentin, pregabalin, memantine, venlafaxine were synthesized and their pharmacological properties to treat neuropathic pain were investigated in a rat model of chronic sciatic nerve constriction injury (CCI). In vivo evaluation demonstrated that the mutual prodrugs 2002413A, 2002823A composed of two gabapentins, 2002414 composed of gabapentin and pregabalin were effective in reversal tactile allodynia in CCI rats. The prodrugs 2002413A, 2002414 had no significant influence on the rotarod activity. The result suggest that the prodrugs may be possible candidates for further development. 相似文献
12.
Dandu RR Gruner JA Mathiasen JR Aimone LD Hostetler G Benfield C Bendesky RJ Marcy VR Raddatz R Hudkins RL 《Bioorganic & medicinal chemistry letters》2011,21(21):6362-6365
A series of pyridazinone-phenethylamine derivatives with moderate to low nanomolar affinity for rat and human H(3)R are described. These analogs exhibited excellent selectivity and metabolic stability, with acceptable rat pharmacokinetic properties. In vivo, 7 and 11 demonstrated potent H(3)R functional antagonism in the rat dipsogenia model and robust wake-promoting activity in the rat electroencephalogram/electromyography (EEG/EMG) model. 相似文献
13.
Becknell NC Lyons JA Aimone LD Huang Z Gruner JA Raddatz R Hudkins RL 《Bioorganic & medicinal chemistry》2012,20(12):3880-3886
A novel series of 4-pyridazin-3-one and 5-pyridazin-3-one analogues were designed and synthesized as H(3)R antagonists. Structure-activity relationship revealed the 5-pyridazin-3-ones 8a and S-methyl 8b had excellent human and rat H(3)R affinities, and acceptable pharmacokinetic properties. In vivo evaluation of 8a showed potent activity in the rat dipsogenia model and robust wake-promoting activity in the rat EEG/EMG model. 相似文献
14.
Birch AM Kenny PW Oikonomakos NG Otterbein L Schofield P Whittamore PR Whalley DP 《Bioorganic & medicinal chemistry letters》2007,17(2):394-399
A series of substituted 3,4-dihydro-2-quinolone glycogen phosphorylase inhibitors, which have potential as antidiabetic agents, is described. Initial members of the series showed good enzyme inhibitory potency but poor physical properties. Optimisation of the 1-substituent led to 2,3-dihydroxypropyl compounds which showed good in vitro potency and improved physical properties, together with good DMPK profiles and acute in vivo efficacy in a rat model. X-ray crystallographic data are presented, showing an unexpected variety of binding orientations at the dimer interface site. 相似文献
15.
Most studies measuring the agonist and antagonist activities of CCK analogs and derivatives on the exocrine pancreas have been done with in vitro models. However, extrapolation to the in vivo situation may be sometimes hazardous, due to the catabolism of the peptides by circulating and tissue peptidases, and to their eventual interaction with various endogenous factors. The present experiments were organized to measure the efficacy and potency on pancreatic secretion of the rat in vivo of a series of CCK 8 analogs whose binding and activity had been previously measured on guinea-pig and rat isolated acini. The molecules tested were derivatives of Boc-(Nle 28-Nle 31)-CCK 26–33 (1), and comprised 2-phenylethylester derivatives, des-Phe derivatives, and a series of pseudo-peptides with a “reduced” bond CH2-NH replacing the peptide bond in position 28–29 to 32–33. They were perfused in anaesthetized rats, and the outputs of sodium, bicarbonate and total protein were measured. All of the derivatives studied had in vivo the same efficacy as (1) on the output of protein, and were 10 to 500 times less potent. For most compounds, the relative order of potencies measured in vivo was similar to that measured in vitro on amylase secretion by rat acini. However, the derivatives with reduced bonds in positions 28–29 and 29–30 were respectively 3 and 2 times less potent in vivo, relative to (1), while derivatives with reduced bonds in positions 30–31, 31–32 and 32–33 were 1.5 to 2.5 times more potent in vivo. The 2-phenylethylester derivatives were 7 and 9 times as potent in vitro as in vivo. The des-Phe derivative, which had in vitro antagonist properties on guinea-pig acini, and acted like a partial agonist on rat acini, was in vivo a complete agonist and was relatively 300 times as potent in vivo as in vitro. These results indicate that the metabolism of the peptides and/or their interaction with endogenous factors may change appreciably the effect of CCK derivatives on pancreatic secretion of the rat in vivo. 相似文献
16.
Yun W Ahmad M Chen Y Gillespie P Conde-Knape K Kazmer S Li S Qian Y Taub R Wertheimer SJ Whittard T Bolin D 《Bioorganic & medicinal chemistry letters》2011,21(23):7205-7209
In a discovery effort to find safe and effective DGAT-1 inhibitors, we have identified 2-phenyloxazole 4-carboxamide 1 as a conformationally constrained analog of a hydrazide hit, which was previously identified from high-throughput screening. Further optimization of this series has led to chemically more stable 2-phenyloxazole-based DGAT-1 inhibitor 25 with improved solubility, cell-based activity, and pharmacokinetic properties. Compound 25 also demonstrated in vivo efficacy in a diet-induced obesity (DIO) rat model. 相似文献
17.
Becknell NC Lyons JA Aimone LD Gruner JA Mathiasen JR Raddatz R Hudkins RL 《Bioorganic & medicinal chemistry letters》2011,21(23):7076-7080
6-{4-[3-(R)-2-Methylpyrrolidin-1-yl)propoxy]-phenyl}-2H-pyridazin-3-one 6 (Irdabisant; CEP-26401) was recently reported as a potent H(3)R antagonist with excellent drug-like properties and in vivo activity that advanced into clinical evaluation. A series of pyridone analogs of 6 was synthesized and evaluated as H(3)R antagonists. Structure-activity relationships revealed that the 5-pyridone regiomer was optimal for H(3)R affinity. N-Methyl 9b showed excellent H(3)R affinity, acceptable pharmacokinetics and pharmaceutical properties. In vivo evaluation of 9b showed potent activity in the rat dipsogenia model and robust wake-promoting activity in the rat EEG model. 相似文献
18.
Zulli AL Aimone LD Mathiasen JR Gruner JA Raddatz R Bacon ER Hudkins RL 《Bioorganic & medicinal chemistry letters》2012,22(8):2807-2810
Optimization of a series of aminomethyl ketone diamine H(3)R antagonists to reduce the brain exposure by lowering the pKa, led to molecules with improved pharmacokinetic properties. Compounds 9, 19, and 25 had high affinity for human H(3)R and demonstrated in vivo H(3)R functional activity in the rat dipsogenia model. Compound 9 displayed modest wake-promoting activity in the rat EEG/EMG model. 相似文献
19.
Magnus Nilsson Anna Karin Belfrage Stefan Lindström Horst Wähling Charlotta Lindquist Susana Ayesa Pia Kahnberg Mikael Pelcman Kurt Benkestock Tatiana Agback Lotta Vrang Ylva Terelius Kristina Wikström Elizabeth Hamelink Christina Rydergård Michael Edlund Anders Eneroth Pierre Raboisson Tse-I Lin Herman de Kock Åsa Rosenquist 《Bioorganic & medicinal chemistry letters》2010,20(14):4004-4011
Novel NS3/4A protease inhibitors comprising quinazoline derivatives as P2 substituent were synthesized. High potency inhibitors displaying advantageous PK properties have been obtained through the optimization of quinazoline P2 substituents in three series exhibiting macrocyclic P2 cyclopentane dicarboxylic acid and P2 proline urea motifs. For the quinazoline moiety it was found that 8-methyl substitution in the P2 cyclopentane dicarboxylic acid series improved on the metabolic stability in human liver microsomes. By comparison, the proline urea series displayed advantageous Caco-2 permeability over the cyclopentane series. Pharmacokinetic properties in vivo were assessed in rat on selected compounds, where excellent exposure and liver-to-plasma ratios were demonstrated for a member of the 14-membered quinazoline substituted P2 proline urea series. 相似文献
20.
The effect of an alternating magnetic field with a magnetic flux density of 150 mT on the blood oxygen-transport function was studied. In vitro exposure of blood cells was performed following a 10-day series of in vivo exposure of the rat tail artery in combination with administration of chemical compounds that affect the formation of gaseous transmitters. In vitro exposure to a magnetic field changed the oxygen-transport function of the blood, as observed by a greater decrease in the affinity of hemoglobin for oxygen and an increase in the concentration of gaseous transmitters (nitric oxide and hydrogen sulfide). In animals to which nitroglycerin and sodium hydrosulfide were administered exposure to a magnetic field caused a shift in the oxyhemoglobin dissociation curve to the right; this effect was absent when a nonselective inhibitor of the NO synthase enzyme or an irreversible inhibitor of the cystathionine γ-lyase enzyme was added. These results suggest that the magnetic field affects the oxygen-binding properties of the blood by modifying intra-erythrocyte mechanisms that involve gaseous transmitters. 相似文献