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21.
Nitric oxide (NO) is synthesized from arginine by three distinct isoforms of nitric oxide synthase (NOS). Two of these isoforms, endothelial NOS (eNOS, type III NOS) and neuronal NOS (nNOS, type I NOS) are expressed in a constitutive manner and are responsible for regulating physiological functions. The induction of the third isoform of nitric oxide synthase (iNOS) by inflammatory processes and the subsequent overproduction of NO is thought to contribute to the tissue damage that occurs in a number of diseases having an inflammatory component, such as sepsis. As a model of sepsis, non-lethal endotoxemia in Hartley guinea pigs was induced using three serotypes of lipopolysaccharide (LPS, 30 mg/kg, i.p.). Each stimulated an increase in total plasma nitrites 6 h following their administration. Treatment orally with two inhibitors of NOS, L-nitroarginine methyl ester (L-NAME), a non-selective inhibitor and N-iminoethyl-L-lysine (L-NIL), a selective iNOS inhibitor, 30 min after the induction of sepsis, inhibited (p < 0.05) the increase in plasma nitrites with ED50 values of 7 ± 1 and 0.4 ± 0.03 mg/kg, respectively, suggesting that NOS inhibitors may be useful in the treatment of human sepsis, or other diseases where excess NO levels have been implicated, such as asthma, arthritis and inflammatory bowel disease. 相似文献
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23.
Reddy MB Connor A Brennan BJ Morcos PN Zhou A McLawhon P Fretland A Evans P Smith P Tran JQ 《Biopharmaceutics & drug disposition》2011,32(5):261-275
Danoprevir, a potent, selective inhibitor of HCV NS3/4A protease, has a short half‐life in humans. Therefore, the feasibility of a controlled release (CR) formulation to allow less frequent dosing was investigated using experimental approaches and physiological modeling to examine whether danoprevir is absorbed in the colon. Danoprevir absorption was studied in portal‐vein‐cannulated monkeys and in monkeys surgically modified to make intraduodenal, intrajejunal, intracolonic and oral administration possible. In portal‐vein‐cannulated monkeys, absorption was apparent up to 24 h after administration. The observed relative bioavailability from intracolonic delivery in the monkey was approximately 30% relative to oral administration, consistent with the model prediction of 40%. Human relative bioavailability for a tablet delivered to the colon compared with an immediate release (IR) formulation was predicted to be 4–28%. Preclinical data and modeling suggested that CR development would be challenging for this Biopharmaceutics Classification System Class IV compound. Therefore, a confirmative study in healthy volunteers was conducted to investigate the relative bioavailability of danoprevir in various regions of the gastrointestinal tract. In a randomized, open‐label, crossover study, subjects received 100 mg danoprevir IR soft gel capsule, 100 mg danoprevir solution delivered to the distal small bowel and colon via an Enterion? capsule (a remotely activated capsule for regional drug delivery) and 100 mg danoprevir powder to the colon via an Enterion? capsule. The relative bioavailability of danoprevir (compared with IR) delivered to the colon was 6.5% for a solution and 0.6% for a powder formulation, indicating that a CR formulation is not feasible. Copyright © 2011 John Wiley & Sons, Ltd. 相似文献
24.
Y Qian M Hamilton A Sidduri S Gabriel Y Ren R Peng R Kondru A Narayanan T Truitt R Hamid Y Chen L Zhang AJ Fretland RA Sanchez KC Chang M Lucas RC Schoenfeld D Laine ME Fuentes CS Stevenson DC Budd 《Journal of medicinal chemistry》2012,55(17):7920-7939
Lysophosphatidic acid is a class of bioactive phospholipid that mediates most of its biological effects through LPA receptors, of which six isoforms have been identified. The recent results from LPA1 knockout mice suggested that blocking LPA1 signaling could provide a potential novel approach for the treatment of idiopathic pulmonary fibrosis. Here, we report the design and synthesis of pyrazole- and triazole-derived carbamates as LPA1-selective and LPA1/3 dual antagonists. In particular, compound 2, the most selective LPA1 antagonist reported, inhibited proliferation and contraction of normal human lung fibroblasts (NHLF) following LPA stimulation. Oral dosing of compound 2 to mice resulted in a dose-dependent reduction of plasma histamine levels in a murine LPA challenge model. Furthermore, we applied our novel antagonists as chemistry probes and investigated the contribution of LPA1/2/3 in mediating the pro-fibrotic responses. Our results suggest LPA1 as the major receptor subtype mediating LPA-induced proliferation and contraction of NHLF. 相似文献
25.
Inger‐Lise Steffensen Adrian J. Fretland Jan Erik Paulsen Yi Feng Tor Jacob Eide Udaya‐Sankar Devanaboyina David W. Hein Jan Alexander 《Basic & clinical pharmacology & toxicology》2000,86(6):257-263
Epidemiological studies indicate that rapid acetylators with a high intake of well‐done red meat have an increased risk of colorectal cancer. Arylamine N‐acetyltransferase enzymes (E.C. 2.3.1.5) activate carcinogenic heterocyclic amines found in the crust of fried meat via O‐acetylation of their N‐hydroxylamines to reactive intermediates that bind covalently to DNA and produce mutations. Syrian hamsters as well as humans express two N‐acetyltransferase isozymes (NAT1 and NAT2) which differ in substrate specificity and genetic control. Nucleic acid substitutions in the NAT2 gene segregate individuals into rapid, intermediate and slow acetylator phenotypes. In the present paper, we examined the role of the polymorphic NAT2 acetylator genotype in carcinogenesis induced by the food mutagens 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine (PhIP) or 2‐amino‐3‐methylimidazo[4,5‐f]quinoline (IQ) by comparing Syrian hamster lines congenic at the NAT2 locus. No differences were found between rapid and slow acetylator congenic hamsters in levels of intestinal PhIP‐DNA adducts. In contrast to previous studies in rats, no carcinogen‐related induction of the preneoplastic lesions aberrant crypt foci or tumors was found in the intestines of rapid and slow acetylator congenic Syrian hamsters administered PhIP or IQ. 相似文献
26.
D. J. Fretland D. L. Widomski C. P. Anglin T. D. Penning S. Yu S. W. Djuric 《Inflammation》1993,17(3):353-360
Leukotriene B4 (LTB4) is a proinflammatory product of arachidonic acid metabolism that has teen implicated as a mediator in a number of inflammatory diseases. When injected intradermally into the guinea pig, LTB4 elicits a dose-dependent migration (chemotaxis) of neutrophils (PMNs) into the injection sites as assessed by the presence of a neutrophil marker enzyme myeloperoxidase. SC-41930 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]-3,4-dihydro-8-propyl-2H-1 -benzopyran-2-carboxylic acid, a first-generation LTB4 receptor antagonist inhibitedthe chemotactic actions of LTB4 when coadministered into the dermal site and when given orally with ED50 values of 340 ng and 1.7 mg/kg, respectively. The secondgeneration LTB4 receptor antagonists SC-50605 7-[3-[2(cyclopropylmethyl)-3-methoxy-4-(4-thiazolyl)phenoxy] propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid and SC-51146 7-[3-[2(cyclopropylmethyl)-3-methoxy-4-[(methylamino)carbonyl]phenoxy]propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran2-propanoic acid inhibited LTB4-induced chemotaxis when coadministered with ED50 values of 70 ng and 32 ng, respectively, and when given intragastrically with ED50 values of 0.10 and 0.09 mg/kg, respectively. SC-41930, SC-50605, and SC-51146 had oral durations of action of 5.5, 15, and 21 h, respectively. These potent, LTB4 receptor antagonists may well have application in the medical management of disease states such as asthma, rheumatoid arthritis, inflammatory bowel disease, contact dermatitis, and psoriasis, where LTB4 is implicated as an inflammatory mediator. 相似文献
27.
Evolution of a highly selective and potent 2-(pyridin-2-yl)-1,3,5-triazine Tie-2 kinase inhibitor 总被引:3,自引:0,他引:3
Hodous BL Geuns-Meyer SD Hughes PE Albrecht BK Bellon S Bready J Caenepeel S Cee VJ Chaffee SC Coxon A Emery M Fretland J Gallant P Gu Y Hoffman D Johnson RE Kendall R Kim JL Long AM Morrison M Olivieri PR Patel VF Polverino A Rose P Tempest P Wang L Whittington DA Zhao H 《Journal of medicinal chemistry》2007,50(4):611-626
Inhibition of angiogenesis is a promising and clinically validated approach for limiting tumor growth and survival. The receptor tyrosine kinase Tie-2 is expressed almost exclusively in the vascular endothelium and is required for developmental angiogenesis and vessel maturation. However, the significance of Tie-2 signaling in tumor angiogenesis is not well understood. In order to evaluate the therapeutic utility of inhibiting Tie-2 signaling, we developed a series of potent and orally bioavailable small molecule Tie-2 kinase inhibitors with selectivity over other kinases, especially those that are believed to be important for tumor angiogenesis. Our earlier work provided pyridinyl pyrimidine 6 as a potent, nonselective Tie-2 inhibitor that was designed on the basis of X-ray cocrystal structures of KDR inhibitors 34 (triazine) and 35 (nicotinamide). Lead optimization resulted in pyridinyl triazine 63, which exhibited >30-fold selectivity over a panel of kinases, good oral exposure, and in vivo inhibition of Tie-2 phosphorylation. 相似文献
28.
Cee VJ Albrecht BK Geuns-Meyer S Hughes P Bellon S Bready J Caenepeel S Chaffee SC Coxon A Emery M Fretland J Gallant P Gu Y Hodous BL Hoffman D Johnson RE Kendall R Kim JL Long AM McGowan D Morrison M Olivieri PR Patel VF Polverino A Powers D Rose P Wang L Zhao H 《Journal of medicinal chemistry》2007,50(4):627-640
The recognition that aberrant angiogenesis contributes to the pathology of inflammatory diseases, cancer, and myocardial ischemia has generated considerable interest in the molecular mechanisms that regulate blood vessel growth. The receptor tyrosine kinase Tie-2 is expressed primarily by vascular endothelial cells and is critical for embryonic vasculogenesis. Interference with the Tie-2 pathway by diverse blocking agents such as soluble Tie-2 receptors, anti-Tie-2 intrabodies, anti-Ang-2 antibodies, and peptide-Fc conjugates has been shown to suppress tumor growth in xenograft studies. An alternative strategy for interfering with the Tie-2 signaling pathway involves direct inhibition of the kinase functions of the Tie-2 receptor. Herein we describe the development of alkynylpyrimidine amide derivatives as potent, selective, and orally available ATP-competitive inhibitors of Tie-2 autophosphorylation. 相似文献
29.
Dietary selenium reduces the formation of aberrant crypts in rats administered 3,2'-dimethyl-4-aminobiphenyl. 总被引:2,自引:0,他引:2
Y Feng J W Finley C D Davis W K Becker A J Fretland D W Hein 《Toxicology and applied pharmacology》1999,157(1):36-42
Human epidemiologic studies suggest that low selenium status is associated with increased cancer risk and that selenium supplementation is associated with reduction in the incidence of several cancers, including colorectal cancer. Aromatic and heterocyclic amine carcinogens are thought to be important in the etiology of human colorectal cancer, but no information is available on the effects of selenium on aromatic amine-induced colon cancer. In order to investigate this effect, aberrant crypt foci (ACF), the putative preneoplastic lesions of colon cancer in humans and rodents, were used as a biomarker to test the hypothesis that selenium supplementation can reduce aromatic amine-induced colon carcinogenesis. Male weanling F344 inbred rats were fed a basal torula yeast selenium-deficient diet supplemented with 0, 0.1, or 2. 0 mg selenium/kg diet as selenite, selenate, or selenomethionine (SeMet). Animals were fed the diets for 4 weeks and then administered 1 sc injection/week for 2 weeks of 3, 2'-dimethyl-4-aminobiphenyl (DMABP; 100 mg/kg) or vehicle (peanut oil). At 12 weeks, the rats were euthanized and the colon and rectum were removed, opened longitudinally, and fixed in 70% ethanol. Glutathione peroxidase activities in erythrocytes and liver cytosol and selenium concentrations in the colon/rectum and kidney increased significantly (p < 0.05) and in a dose-dependent manner with each of the three selenium diets. No ACF were identified in vehicle-treated rats. In DMABP-treated rats, ACF frequencies decreased significantly (p < 0.05) in groups supplemented with 0.1 or 2.0 mg selenium/kg diet as selenite and selenate but not SeMet. There were no significant differences in ACF and aberrant crypts between rats fed 0.1 vs 2.0 mg selenium/kg diet. These results suggest that dietary selenium, depending on chemical form, can reduce aromatic amine-induced colon carcinogenesis. 相似文献
30.
Genetic polymorphism in N-acetyltransferase-1 (NAT1) is associated with increased risk of various cancers, but epidemiological investigations are compromised by poor understanding of the relationship between NAT1 genotype and phenotype. Human reference NAT1*4 and 12 known human NAT1 allelic variants possessing nucleotide polymorphisms in the NAT1 coding region were cloned and expressed in yeast (Schizosaccharomyces pombe). Large reductions in the N-acetylation of 4-aminobiphenyl and the O-acetylation of N-hydroxy-2-aminofluorene were observed for recombinant NAT1 allozymes encoded by NAT1*14B, NAT1*15, NAT1*17, NAT1*19, and NAT1*22. Each of these alleles exhibited substantially lower expression of NAT1 protein than the reference NAT1*4 and the other NAT1 alleles. These results show an important effect of the NAT1 genetic polymorphism on the N- and O-acetylation of arylamine carcinogens, suggesting modification of cancer susceptibility following exposures to arylamine carcinogens. 相似文献