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Synthesis and biological evaluation of BMS-986120 and its deuterated derivatives as PAR4 antagonists
Panpan Chen Shenhong Ren Hangyu Song Cai Chen Fangjun Chen Qinglong Xu Yi Kong Hongbin Sun 《Bioorganic & medicinal chemistry》2019,27(1):116-124
BMS-986120 is a PAR4 antagonist that is being investigated as an antiplatelet agent in phase I clinical trial. An improved synthesis of BMS-986120 has been developed. Based on the novel synthetic approach to BMS-986120, a series of deuterated derivatives of BMS-986120 have been synthesized and biologically evaluated to search for more potent antiplatelet agents. The in vitro antiplatelet assay by turbidimetry demonstrated that PC-2 and PC-6 had IC50 values of 6.30?nM and 6.97?nM, respectively, versus BMS-986120 with an IC50 of 7.80?nM. The result of in vitro metabolic stability study showed that all of the deuterated compounds had similar half-life (T1/2) and intrinsic clearance (Clint) in comparison with BMS-986120. Further probing the metabolic profile of BMS-986120 is worth being conducted. 相似文献
995.
Purinergic activation of spontaneous transient outward currents in guinea pig taenia colonic myocytes 总被引:10,自引:0,他引:10
Spontaneous transient outward currents(STOCs) were recorded from smooth muscle cells of theguinea pig taenia coli using the whole cell patch-clamp technique.STOCs were resolved at potentials positive to 50 mV. Treatingcells with caffeine (1 mM) caused a burst of outward currentsfollowed by inhibition of STOCs. Replacing extracellularCa2+ with equimolarMn2+ caused STOCs to "rundown." Iberiotoxin (200 nM) or charybdotoxin (ChTX; 200 nM)inhibited large-amplitude STOCs, but small-amplitude "mini-STOCs"remained in the presence of these drugs. Mini-STOCs were reduced byapamin (500 nM), an inhibitor of small-conductance Ca2+-activatedK+ channels (SK channels).Application of ATP or 2-methylthioadenosine 5'-triphosphate(2-MeS-ATP) increased the frequency of STOCs. The effects of 2-MeS-ATPpersisted in the presence of charybdotoxin but were blocked bycombination of ChTX (200 nM) and apamin (500 nM). 2-MeS-ATP did notincrease STOCs in the presence of pyridoxal phosphate6-azophenyl-2',4'-disulfonic acid, aP2 receptor blocker. Similarly,pretreatment of cells with U-73122 (1 µM), an inhibitor ofphospholipase C (PLC), abolished the effects of 2-MeS-ATP. XestosponginC, an inositol 1,4,5-trisphosphate(IP3) receptor blocker,attenuated STOCs, but these events were not affected by ryanodine. Thedata suggest that purinergic activation through P2Y receptors results in localizedCa2+ release via PLC- andIP3-dependent mechanisms. Releaseof Ca2+ is coupled to STOCs, whichare composed of currents mediated by large-conductanceCa2+-activatedK+ channels and SK channels. Thelatter are thought to mediate hyperpolarization and relaxationresponses of gastrointestinal muscles to inhibitory purinergic stimulation. 相似文献
996.
Applied anatomy of the anterolateral femoral flap 总被引:13,自引:0,他引:13
D C Xu S Z Zhong J M Kong G Y Wang M Z Liu L S Luo J H Gao 《Plastic and reconstructive surgery》1988,82(2):305-310
A study of the source of the blood supply to the anterolateral femoral flap was carried out on 42 lower limbs of adult cadavers (among them 35 cadavers with injection of red latex and 1 with india ink into the arteries and 6 vascular cast specimens), and the surface locations of the vascular pedicle were detected on 50 healthy adults. It was found that the descending branch of the lateral circumflex femoral vessel was an ideal axial vessel. There are constant perforating branches of the myocutaneous artery or cutaneous branches from the intermuscular space to the anterolateral femoral skin. The area extends about 12 x 30 cm. Within the flap, the anterior branch of the anterolateral cutaneous nerve of the high is located. This flap has been widely used for free transplantation in China since 1983 with satisfactory results. 相似文献
997.
HongKyung Kim Harinarayana Ankamreddy Dong Jin Lee Kyoung-Ah Kong Hyuk Wan Ko Myoung Hee Kim Jinwoong Bok 《Biochemical and biophysical research communications》2014
Pax3 mutations result in malformed inner ears in Splotch mutant mice and hearing loss in humans with Waardenburg’s syndrome type I. In the inner ear, Pax3 is thought to be involved mainly in the development of neural crest. However, recent studies have shown that Pax3-expressing cells contribute extensively to multiple inner ear structures, some of which were considered to be derived from the otic epithelium. To examine the specific functions of Pax3 during inner ear development, fate mapping of Pax3 lineage was performed in the presence or absence of functional Pax3 proteins using Pax3Cre knock-in mice bred to Rosa26 reporter (R26R) line. β-gal-positive cells were widely distributed in Pax3Cre/+; R26R inner ears at embryonic day (E) 15.5, including the endolymphatic duct, common crus, cristae, maculae, cochleovestibular ganglion, and stria vascularis. In the absence of Pax3 in Pax3Cre/Cre; R26R inner ears, β-gal-positive cells disappeared from regions with melanocytes such as the stria vascularis of the cochlea and dark cells in the vestibule. Consistently, the expression of Dct, a melanoblast marker, was also absent in the mutant inner ears. However, when examined at E11.5, β-gal positive cells were present in Pax3Cre/Cre mutant otocysts, whereas Dct expression was absent, suggesting that Pax3 lineage with a melanogenic fate migrated to the inner ear, yet failed to differentiate and survive without Pax3 function. Gross inner ear morphology was generally normal in Pax3Cre/Cre mutants, unless neural tube defects extended to the cranial region. Taken together, these results suggest that despite the extensive contribution of Pax3-expressing cells to multiple inner ear tissues, Pax3 function is required specifically for inner ear components with melanogenic fates. 相似文献
998.
Xiang Li Chang Yu Yichun Luo Jiacheng Lin Fang Wang Xuehua Sun Yueqiu Gao Weifeng Tan Qiang Xia Xiaoni Kong 《International journal of biological sciences》2021,17(7):1782
Energy metabolism reprogramming has been implicated in tumorigenesis and development. Key metabolism enzyme Aldolase A (ALDOA) has been shown to be highly expressed and involved in various kinds of cancers including hepatocellular carcinoma. In this study, we found that ALDOA was highly expressed in clinical intrahepatic cholangiocarcinoma (ICC) tissues, and its high expression was negatively correlated with overall survival (OS) and recurrence-free survival (RFS) in ICC patients. Knockdown of ALDOA expression significantly inhibited the proliferation and migration of ICC both in vitro and in vivo, while highly-expressed ALDOA in ICC cells promoted the proliferation and migration of ICC cells. By applying ALDOA inhibitor and metabolic mass spectrometry tests, we demonstrated that ALDOA modulated the biological characteristics and metabolic level of ICC cells depending on its enzymatic activity. In summary, ALDOA promotes ICC proliferation and migration by enhancing ICC cells glycolysis. Blocking enzymatic activity of ALDOA provides a strategy to inhibit ICC. 相似文献
999.
Wang H Huang Z Huang L Niu S Rao X Xu J Kong H Yang J Yang C Wu D Li S Li XJ Liu T Sheng G 《The Journal of biological chemistry》2012,287(3):2237-2246
It is indicated that there are important molecules interacting with brain nervous systems to regulate feeding and energy balance by influencing the signaling pathways of these systems, but relatively few of the critical players have been identified. In the present study, we provide the evidence for the role of Abelson helper integration site 1 (Ahi1) protein as a mediator of feeding behavior through interaction with serotonin receptor 2C (5-HT(2C)R), known for its critical role in feeding and appetite control. First, we demonstrated the co-localization and interaction between hypothalamic Ahi1 and 5-HT(2C)R. Ahi1 promoted the degradation of 5-HT(2C)R through the lysosomal pathway. Then, we investigated the effects of fasting on the expression of hypothalamic Ahi1 and 5-HT(2C)R. Fasting resulted in an increased Ahi1 expression and a concomitant decreased expression of 5-HT(2C)R. Knockdown of hypothalamic Ahi1 led to a concomitant increased expression of 5-HT(2C)R and a decrease of food intake and body weight. Last, we found that Ahi1 could regulate the expression of neuropeptide Y and proopiomelanocortin. Taken together, our results indicate that Ahi1 mediates feeding behavior by interacting with 5-HT(2C)R to modulate the serotonin signaling pathway. 相似文献
1000.
Effect of serum starvation on the efficiency of nuclear transfer using odd-eyed white cat fibroblasts 总被引:3,自引:0,他引:3
In the present study, we compared in vitro and in vivo development of nuclear transfer (NT) embryos derived from serum-starved or non-serum-starved odd-eyed cat skin fibroblast cells. Flow cytometry analyses revealed that a higher percentage of cells were in the G0/G1 phase after serum starvation (89.3%) as compared with non-serum-starved cells (73.8%, P<0.05). Frequency of cleavage and development to the blastocyst stage was not different between the serum-starved or non-serum-starved treatment group, 67.9 and 12.5% versus 73.0 and 10.2%, respectively (P>0.05). After transfer of two to four-cell NT embryos derived from starved and non-starved fibroblasts, three of nine (33%) and one of nine (11%) recipients delivered three live male (plus, one dead) and two live male kittens, respectively. Of the five live-cloned kittens, one died from diarrhea at 3 weeks of age and the other four kittens are growing at a normal rate. The cloned kittens are blue-eyed and have functional auditory systems, including clones of the odd-eyed deaf Turkish Angora cat. Subsequent DNA analysis of nine-cat specific microsatellite loci confirmed that all of the cloned kittens were identical to the odd-eyed donor male, but a point mutation occurred in the dead fetus at the FCA 290 marker. 相似文献