共查询到20条相似文献,搜索用时 31 毫秒
1.
Ian M. Bell Rodney A. Bednar Halea A. Corcoran John F. Fay Steven N. Gallicchio Victor K. Johnston James C. Hershey Cynthia M. Miller-Stein Eric L. Moore Scott D. Mosser Shane A. Roller Christopher A. Salvatore Cory R. Theberge Bradley K. Wong C. Blair Zartman Stefanie A. Kane Theresa M. Williams Samuel L. Graham Joseph P. Vacca 《Bioorganic & medicinal chemistry letters》2009,19(16):4740-4742
A series of tricyclic CGRP receptor antagonists was optimized in order to improve oral bioavailability. Attenuation of polar surface area and incorporation of a weakly basic indoline nitrogen led to compound 5, a potent antagonist with good oral bioavailability in three species. 相似文献
2.
Scherman MS North EJ Jones V Hess TN Grzegorzewicz AE Kasagami T Kim IH Merzlikin O Lenaerts AJ Lee RE Jackson M Morisseau C McNeil MR 《Bioorganic & medicinal chemistry》2012,20(10):3255-3262
Adamantyl ureas were previously identified as a group of compounds active against Mycobacterium tuberculosis in culture with minimum inhibitor concentrations (MICs) below 0.1 μg/ml. These compounds have been shown to target MmpL3, a protein involved in secretion of trehalose mono-mycolate. They also inhibit both human soluble epoxide hydrolase (hsEH) and M. tuberculosis epoxide hydrolases. However, active compounds to date have high cLogP's and are poorly soluble, leading to low bioavailability and thus limiting any therapeutic application. In this study, a library of 1600 ureas (mostly adamantyl ureas), which were synthesized for the purpose of increasing the bioavailability of inhibitors of hsEH, was screened for activity against M. tuberculosis. 1-Adamantyl-3-phenyl ureas with a polar para substituent were found to retain moderate activity against M. tuberculosis and one of these compounds was shown to be present in serum after oral administration to mice. However, neither it, nor a closely related analog, reduced M. tuberculosis infection in mice. No correlation between in vitro potency against M. tuberculosis and the hsEH inhibition were found supporting the concept that activity against hsEH and M. tuberculosis can be separated. Also there was a lack of correlation with cLogP and inhibition of the growth of M. tuberculosis. Finally, members of two classes of adamantyl ureas that contained polar components to increase their bioavailability, but lacked efficacy against growing M. tuberculosis, were found to taken up by the bacterium as effectively as a highly active apolar urea suggesting that these modifications to increase bioavailability affected the interaction of the urea against its target rather than making them unable to enter the bacterium. 相似文献
3.
Bell IM Bednar RA Fay JF Gallicchio SN Hochman JH McMasters DR Miller-Stein C Moore EL Mosser SD Pudvah NT Quigley AG Salvatore CA Stump CA Theberge CR Wong BK Zartman CB Zhang XF Kane SA Graham SL Vacca JP Williams TM 《Bioorganic & medicinal chemistry letters》2006,16(24):6165-6169
A rapid analogue approach to identification of spirohydantoin-based CGRP antagonists provided novel, low molecular weight leads. Modification of these leads afforded a series of nanomolar benzimidazolinone-based CGRP receptor antagonists. The oral bioavailability of these antagonists was inversely correlated with polar surface area, suggesting that membrane permeability was a key limitation to absorption. Optimization provided compound 12, a potent CGRP receptor antagonist (Ki = 21 nM) with good oral bioavailability in three species. 相似文献
4.
Luo G Chen L Civiello R Pin SS Xu C Kostich W Kelley M Conway CM Macor JE Dubowchik GM 《Bioorganic & medicinal chemistry letters》2012,22(8):2917-2921
In our continuing efforts to identify CGRP receptor antagonists that can be dosed orally for the treatment of migraine headache, we have investigated a pyridine bioisosteric replacement of a polar amide portion of a previous lead compound, BMS-694153. Pyridine derivatives were discovered and their SAR was studied. Some of them showed excellent binding potency. However, oral bioavailability was low, even for compounds with good Caco-2 cell permeability. 相似文献
5.
Bueno JM Manzano P García MC Chicharro J Puente M Lorenzo M García A Ferrer S Gómez RM Fraile MT Lavandera JL Fiandor JM Vidal J Herreros E Gargallo-Viola D 《Bioorganic & medicinal chemistry letters》2011,21(18):5214-5218
Antimalarial 4-pyridones are a novel class of inhibitors of the plasmodial mitochondrial electron transport chain targeting Cytochrome bc1 (complex III). In general, the most potent 4-pyridones are lipophilic molecules with poor solubility in aqueous media and low oral bioavailability in pre-clinical species from the solid dosage form. The strategy of introducing polar hydroxymethyl groups has enabled us to maintain the high levels of antimalarial potency observed for other more lipophilic analogues whilst improving the solubility and the oral bioavailability in pre-clinical species. 相似文献
6.
Tanaka M Sagawa S Hoshi J Shimoma F Yasue K Ubukata M Ikemoto T Hase Y Takahashi M Sasase T Ueda N Matsushita M Inaba T 《Bioorganic & medicinal chemistry》2006,14(17):5781-5794
Conformationally restricted 3-anilino-4-(3-indolyl)maleimide derivatives were designed and synthesized aiming at discovery of novel protein kinase Cbeta (PKCbeta)-selective inhibitors possessing oral bioavailability. Among them, compounds having a fused five-membered ring at the indole 1,2-position inhibited PKCbeta2 with IC50 of nM-order and showed good oral bioavailability. One of the most potent compounds was found to be PKCbeta-selective over other 6 isozymes and exhibited ameliorative effects in a rat diabetic retinopathy model via oral route. 相似文献
7.
Li X Zhang S Zhang YK Liu Y Ding CZ Zhou Y Plattner JJ Baker SJ Bu W Liu L Kazmierski WM Duan M Grimes RM Wright LL Smith GK Jarvest RL Ji JJ Cooper JP Tallant MD Crosby RM Creech K Ni ZJ Zou W Wright J 《Bioorganic & medicinal chemistry letters》2011,21(7):2048-2054
We have synthesized and evaluated a new series of acyclic P4-benzoxaborole-based HCV NS3 protease inhibitors. Structure-activity relationships were investigated, leading to the identification of compounds 5g and 17 with low nanomolar potency in the enzymatic and cell-based replicon assay. The linker-truncated compound 5j was found to exhibit improved absorption and oral bioavailability in rats, suggesting that further reduction of molecular weight and polar surface area could result in improved drug-like properties of this novel series. 相似文献
8.
Peter J. Choi Hamish S. Sutherland Amy S.T. Tong Adrian Blaser Scott G. Franzblau Christopher B. Cooper Manisha U. Lotlikar Anna M. Upton Jerome Guillemont Magali Motte Laurence Queguiner Koen Andries Walter Van den Broeck William A. Denny Brian D. Palmer 《Bioorganic & medicinal chemistry letters》2017,27(23):5190-5196
Analogues of bedaquiline where the phenyl B-unit was replaced with monocyclic heterocycles of widely differing lipophilicity (thiophenes, furans, pyridines) were synthesised and evaluated. While there was an expected broad positive correlation between lipophilicity and anti-TB activity, the 4-pyridyl derivatives appeared to have an additional contribution to antibacterial potency. The majority of the compounds were (desirably) more polar and had higher rates of clearance than bedaquiline, and showed acceptable oral bioavailability, but there was only limited (and unpredictable) improvement in their hERG liability. 相似文献
9.
The purpose of this research was to prepare acyclovir niosomes in a trial to improve its poor and variable oral bioavailability. The nonionic surfactant vesicles were prepared by the conventional thin film hydration method. The lipid mixture consisted of cholesterol, span 60, and dicetyl phosphate in the molar ratio of 65:60:5, respectively. The percentage entrapment was approximately 11% of acyclovir used in the hydration process. The vesicles have an average size of 0.95 microm, a most probable size of 0.8 microm, and a size range of 0.4 to 2.2 microm. Most of the niosomes have unilamellar spherical shape. In vitro drug release profile was found to follow Higuchi's equation for free and niosomal drug. The niosomal formulation exhibited significantly retarded release compared with free drug. The in vivo study revealed that the niosomal dispersion significantly improved the oral bioavailability of acyclovir in rabbits after a single oral dose of 40 mg kg(-1). The average relative bioavailability of the drug from the niosomal dispersion in relation to the free solution was 2.55 indicating more than 2-fold increase in drug bioavailability. The niosomal dispersion showed significant increase in the mean residence time (MRT) of acyclovir reflecting sustained release characteristics. In conclusion, the niosomal formulation could be a promising delivery system for acyclovir with improved oral bioavailability and prolonged drug release profiles. 相似文献
10.
11.
Ho KK Auld DS Bohnstedt AC Conti P Dokter W Erickson S Feng D Inglese J Kingsbury C Kultgen SG Liu RQ Masterson CM Ohlmeyer M Rong Y Rooseboom M Roughton A Samama P Smit MJ Son E van der Louw J Vogel G Webb M Wijkmans J You M 《Bioorganic & medicinal chemistry letters》2006,16(10):2724-2728
An imidazolylpyrimidine was identified in a CXCR2 chemokine receptor antagonist screen and was optimized for potency, in vitro metabolic stability, and oral bioavailability. It was found that subtle structural modification within the series affected the oral bioavailability. Potent and orally available CXCR2 antagonists are herein reported. 相似文献
12.
Buchanan CM Buchanan NL Edgar KJ Little JL Ramsey MG Ruble KM Wacher VJ Wempe MF 《Biomacromolecules》2008,9(1):305-313
The current research evaluated the ability of hydroxybutenyl-beta-cyclodextrin (HBenBCD) to enhance saquinavir in vitro solubility and in vivo oral bioavailability; both the base and mesylate salt forms of saquinavir were investigated. HBenBCD was effective and significantly improved saquinavir solubility in aqueous media. In the presence of 10 wt % HBenBCD, saquinavir base solubility in water was increased to ca. 5.5 +/- 0.4 mg/mL and represents a 27-fold increase from that observed in water (207 +/- 5 microg/mL) in the absence of HBenBCD. Saquinavir-HBenBCD formulations were found to have rapid dissolution over a wide pH range (1.2-6.8), and saquinavir solubility in these media was maintained throughout the experiments. When saquinavir-HBenBCD formulations were administered to Wistar-Hannover rats, saquinavir was rapidly absorbed and rapidly eliminated. Rapid saquinavir elimination was particularly pronounced when saquinavir-HBenBCD formulations were given as an oral aqueous gavage. Saquinavir oral bioavailability in rats obtained from saquinavir mesylate capsules (2.0% +/- 0.7%) was increased (9 +/- 4)-fold (18.6% +/- 7.3%) when dosed with saquinavir base-HBenBCD capsules. Clearly, HBenBCD can significantly improve the solubility and oral bioavailability of saquinavir; however, further formulation studies are required to optimize saquinavir oral delivery using this technology. 相似文献
13.
Murali Mohan Babu GV Kumar NR Sankar KH Ram BJ Kumar NK Murthy KV 《AAPS PharmSciTech》2002,3(2):55-63
This work examines the influence of modified gum karaya (MGK) on the oral bioavailability of a poorly water-soluble drug,
nimodipine (NM), in comparison with that of gum karaya (GK). A cogrinding method was selected to prepare mixtures of NM and
GK or MGK in a 1:9 ratio (NM:GK/MGK). Differential scanning calorimetry (DSC), Fourier transmission infrared (FT-IR) spectroscopy,
X-ray diffraction (XRD), solubility studies, and in vitro release studies were performed to characterize the properties of
the cogrinding mixtures. No drug-carrier interactions were found, as confirmed by DSC and FT-IR studies. The XRD study revealed
that the crystallinity of NM was identical in both the cogrinding mixtures and was decreased when compared to that of physical
mixtures or pure NM. The in vitro release rate of NM from both cogrinding mixtures was significantly higher than that of physical
mixtures or pure NM. The in vivo study revealed that the bioavailability of NM from pure drug was significantly lower when
compared to the cogrinding mixtures. The oral bioavailability was found to be NM powder < cogrinding mixtures of NM and GK
< cogrinding mixtures of NM and MGK < NM solution. It can be inferred from the above results that MGK, an economical carrier,
could be used for the dissolution enhancement of NM. 相似文献
14.
The main purpose of this work was to develop an oral microemulsion formulation for enhancing the bioavailability of acyclovir.
A Labrafac-based microemulsion formulation with Labrasol as surfactant and Plurol Oleique as cosurfactant was developed for
oral delivery of acyclovir. Phase behavior and solubilization capacity of the microemulsion system were characterized, and
in vivo oral absorption of acyclovir from the microemulsion was investigated in rats. A single isotropic region, which was
considered to be a bicontinuous microemulsion, was found in the pseudoternary phase diagrams developed at various Labrasol:Plurol
Oleique:Labrafac ratios. With the increase of Labrasol concentration, the microemulsion region area and the amount of water
and Labrafac solubilized into the microemulsion system increased; however, the increase of Plurol Oleique percentage produced
opposite effects. The microemulsion system was also investigated in terms of other characteristics, such as interfacial tension,
viscosity, pH, refractive index, diffusion, and bioavailability. Acyclovir, a poorly soluble drug, displayed high solubility
in a microemulsion formulation using Labrafac (10%). Labrasol (32%), Plurol Oleique (8%), and water (50%). The in vitro intraduodenal
diffusion and in vivo study revealed an increase of bioavailability (12.78 times) after oral administration of the microemulsion
formulation as compared with the commercially available tablets.
Published: September 15, 2006 相似文献
15.
Hitesh K. Patel Robert M. Grotzfeld Andiliy G. Lai Shamal A. Mehta Zdravko V. Milanov Qi Chao Kelly G. Sprankle Todd A. Carter Anne Marie Velasco Miles A. Fabian Joyce James Daniel K. Treiber David J. Lockhart Patrick P. Zarrinkar Shripad S. Bhagwat 《Bioorganic & medicinal chemistry letters》2009,19(17):5182-5185
A series of diaryl ureas with an amide substitution at the 4-position was prepared and found to be potent and selective FLT3 inhibitors with good oral bioavailability and efficacy in a tumor xenograft model. 相似文献
16.
A self-microemulsifying drug delivery system (SMEDDS) has been developed to enhance diffusion rate and oral bioavailability
of valsartan. The solubility of valsartan was checked in different oils, surfactants, and cosurfactants and ternary phase
diagrams were constructed to evaluate the microemulsion domain. The valsartan SMEDDS was prepared using Capmul MCM (oil),
Tween 80 (surfactant), and polyethylene glycol 400 (cosurfactant). The particle size distribution, zeta potential, and polydispersity
index were determined and were found to be 12.3 nm, −0.746, and 0.138, respectively. Diffusion rate of valsartan was measured
by in vitro dialysis bag method using phosphate buffer pH 6.8 as diffusion media. Developed high-performance liquid chromatography method
was used to determine drug content in diffusion media. Oral bioavailability of valsartan SMEDDS was checked by using rabbit
model. Results of diffusion rate and oral bioavailability of valsartan SMEDDS were compared with those of pure drug solution
and of marketed formulation. Diffusion of valsartan SMEDDS showed maximum drug release when compared to pure drug solution
and marketed formulation. The area under curve and time showed significant improvement as the values obtained were 607 ng h/mL
and 1 h for SMEDDS in comparison to 445.36 and 1.36 h for market formulation suggesting significant increase (p < 0.01) in oral bioavailability of valsartan SMEDDS. 相似文献
17.
Preparation and Enhanced Oral Bioavailability of Cryptotanshinone-Loaded Solid Lipid Nanoparticles 总被引:1,自引:0,他引:1
In this study, solid lipid nanoparticles (SLNs) were successfully prepared by an ultrasonic and high-pressure homogenization
method to improve the oral bioavailability of the poorly water-soluble drug cryptotanshinone (CTS). The particle size and
distribution, drug loading capacity, drug entrapment efficiency, zeta potential, and long-term physical stability of the SLNs
were characterized in detail. A pharmacokinetic study was conducted in rats after oral administration of CTS in different
SLNs, and it was found that the relative bioavailability of CTS in the SLNs was significantly increased compared with that
of a CTS-suspension. The incorporation of CTS in SLNs also markedly changes the metabolism behavior of CTS to tanshinone IIA.
These results indicate that CTS absorption is enhanced significantly by employing SLN formulations, and SLNs represent a powerful
approach for improving the oral absorption of poorly soluble drugs. 相似文献
18.
The influence of feeding on the bioavailability of oxytetracycline was studied in preruminant calves. Oxytetracycline was given in water as a drench to fasting calves or was mixed in the milk replacer. Compared to water the bioavailability was significantly reduced (53.5%) when oxytetracycline was mixed in the milk re-placer. A further reduction, 83.3 %, occurred when the calves were treated one hour post milk feeding. Also concentrate was found to reduce the bioavailability. Very high serum levels were recorded when the drug was given in an oral rehydration solution, pH 4.9, containing glycine. The values obtained when an alkaline (pH 8.3) solution without glycine was used did not differ from the levels recorded when oxytetracycline was given in water. It was suggested that the use of oxytetra-cyclines in feeds may be questioned because of their well-known complex forming ability. 相似文献
19.
Poonam Singh Thakur Narinder Singh Abhay T. Sangamwar Arvind Kumar Bansal 《AAPS PharmSciTech》2017,18(7):2529-2540
Bioenhancers can increase the bioavailability of metabolism susceptible drugs. The present study was designed to understand the impact of bioenhancer on permeability and bioavailability of a biopharmaceutical drug disposition classification system (BDDCS) class II drug raloxifene (RLX). RLX undergoes extensive first pass metabolism by UGT enzymes in gastrointestinal tract (GIT) and has an oral bioavailability of about 2%. Self-emulsifying drug delivery system (SEDDS) of RLX was developed using a designed approach and this formulation was loaded with reported bioenhancers: quercetin and piperine. These formulations were tested for improvement in permeability and bioavailability of the RLX. The apparent permeability using everted gut sac (P app) for SEDDS (5.26?±?1.10?×?10?8 cm/s) was found to be similar to that of SEDDS with bioenhancers (5.11?±?1.05?×?10?8 cm/s). In oral bioavailability study in rat, SEDDS demonstrated a 4-fold and 2.5-fold higher AUC0–∞ than RLX suspension (control) and marketed product, respectively. No additional improvement in permeability and bioavailability was offered by inclusion of piperine and quercetin (bioenhancers) in the SEDDS. 相似文献
20.
F M Martin R P Beckett C L Bellamy P F Courtney S J Davies A H Drummond R Dodd L M Pratt S R Patel M L Ricketts R S Todd A R Tuffnell J W Ward M Whittaker 《Bioorganic & medicinal chemistry letters》1999,9(19):2887-2892
Novel sulfonamide matrix metalloproteinase inhibitors of general formula (9) were synthesised by a route involving a stereoselective conjugate addition reaction. Enzyme selectivity was found to be dependant on the nature of the sulfonamide substituents. Compounds (9f, 9q) are potent selective collagenase inhibitors with good oral bioavailability. 相似文献