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1.
J Phys Condens Matter ; 34(41)2022 Aug 04.
Article in English | MEDLINE | ID: mdl-35901791

ABSTRACT

In this paper, a phase-field model of Si-doped hafnium oxide-based ferroelectric thin films is established. And then, the synergistic effect of Si concentration and distribution on ferroelectric properties optimization of Si:HfO2ferroelectric thin films is studied with the proposed model. It is found that no matter how Si dopant is distributed in the film, the volume fraction of the ferroelectric phase in the film increases first and then decreases with the increase of Si concentration. However, compared with the uniform distribution, the layered distribution is more likely to great improve ferrelectric properties. When Si dopant is uniformly distributed in the film, the highest remanent polarization value that the film can obtain via Si concentration modulation is 38.7µC cm-2, and the corresponding Si concentration is 3.8 cat%, which is consistent with the experimental results. When Si dopant is layered in the film, and the concentration difference between the Si-rich and Si-poor layers is 7.6%, in the Si concentration range of 3.6 cat%-3.8 cat%, the residual polarization of the film reaches 46.4-46.8µC cm-2, which is 20% higher than that when Si dopant are evenly distributed in the film. The above results show that selecting the Si layered distribution mode and controlling the concentration difference between Si-rich and Si-poor layers in an appropriate range can greatly improve the films' ferroelectric properties and broaden the Si concentration optimization range of the ferroelectric properties of the films. The result provides further theoretical guidance on using Si doping to adjust the ferroelectric properties of hafnium oxide-based films.

2.
Minim Invasive Ther Allied Technol ; 31(5): 747-752, 2022 Jun.
Article in English | MEDLINE | ID: mdl-33719842

ABSTRACT

PURPOSE: To assess the effectiveness and safety of irradiation stent insertion for patients with distal biliary obstruction (DBO) secondary to primary common biliary cancer. MATERIAL AND METHODS: Eighty-two consecutive patients with DBO secondary to primary common biliary cancer were treated via either normal (n = 45) or irradiation stenting (n = 37) between January 2013 and December 2019. The instant and long-term outcomes were compared. RESULTS: Technical success rates of normal and irradiation stenting were both 100%. Clinical success rates of normal and irradiation stenting were 91.1 and 100%, respectively (p = .179). Stent reobstruction was observed in 13 and 7 patients in the normal and irradiation stenting groups, respectively (p = .295). The median stent patency was 162 and 225 days in the normal and irradiation stenting groups, respectively (p < .001). The median survival was 178 and 250 days in the normal and irradiation stenting groups, respectively (p < .001). Cholangitis was, respectively, observed in 8 and 12 patients in normal and irradiation stenting groups (p = .124). CONCLUSION: Irradiation stenting is effective and safe for patients with DBO secondary to primary common biliary cancer and can prolong stent patency and survival.


Subject(s)
Bile Duct Neoplasms , Biliary Tract Neoplasms , Cholestasis , Bile Duct Neoplasms/complications , Biliary Tract Neoplasms/complications , Biliary Tract Neoplasms/radiotherapy , Biliary Tract Neoplasms/surgery , Cholestasis/etiology , Cholestasis/surgery , Humans , Retrospective Studies , Stents , Treatment Outcome
3.
Soft Matter ; 17(39): 8850-8857, 2021 Oct 13.
Article in English | MEDLINE | ID: mdl-34533557

ABSTRACT

In this work, we report a simple strategy to readily prepare poly(3-butylthiophene) (P3BT) films with patterned spherulites by brushing the P3BT film surface and annealing the film with carbon disulfide (CS2) vapor. The spherulites nucleated preferentially at the mechanically scratched areas over the unscratched region of the film. The ridge (formed at the side of the scratch) hinders the diffusion of the P3BT molecules, promoting the aggregation and nucleation of P3BT along the ridge to form spherulites upon the CS2 vapor-annealing. The sizes of the ridge and the scratch have no effect on the nucleation and crystallization of the patterned spherulites. We evaluated the crack formation of the P3BT films with patterned spherulites in response to mechanical stretching along different directions. When the stretching direction was parallel to the scratching direction, cracks appeared preferentially at the boundary between the ordered spherulites. In contrast, cracks occurred first at the boundary of stochastic nucleated spherulites located away from the patterned spherulites, when the stretching direction was perpendicular to the scratching direction. The patterned spherulites with regulated mechanical properties may find applications in the design and fabrication of stretchable organic optoelectronic devices with enhanced stability and durability.

4.
ACS Appl Mater Interfaces ; 10(17): 14894-14900, 2018 May 02.
Article in English | MEDLINE | ID: mdl-29637767

ABSTRACT

The effect of shell thickness on the performance of all-inorganic quantum dot light-emitting diodes (QLEDs) is explored by employing a series of green quantum dots (QDs) (Zn xCd1- xSe/ZnS core/shell QDs with different ZnS shell thicknesses) as the emitters. ZnO nanoparticles and sol-gel NiO are employed as the electron and hole transport materials, respectively. Time-resolved and steady-state photoluminescence results indicate that positive charging processes might occur for the QDs deposited on NiO, which results in emission quenching of QDs and poor device performance. The thick shell outside the core in QDs not only largely suppresses the QD emission quenching but also effectively preserves the excitons in QDs from dissociation of electron-hole pairs when they are subjected to an electric field. The peak efficiency of 4.2 cd/A and maximum luminance of 4205 cd/m2 are achieved for the device based on QDs with the thickest shells (∼4.2 nm). We anticipate that these results will spur progress toward the design and realization of efficient all-inorganic QLEDs as a platform for the QD-based full-colored displays.

5.
J Med Chem ; 60(22): 9162-9183, 2017 11 22.
Article in English | MEDLINE | ID: mdl-28892380

ABSTRACT

Inhibition of the bromodomain of the transcriptional regulator CBP/P300 is an especially interesting new therapeutic approach in oncology. We recently disclosed in vivo chemical tool 1 (GNE-272) for the bromodomain of CBP that was moderately potent and selective over BRD4(1). In pursuit of a more potent and selective CBP inhibitor, we used structure-based design. Constraining the aniline of 1 into a tetrahydroquinoline motif maintained potency and increased selectivity 2-fold. Structure-activity relationship studies coupled with further structure-based design targeting the LPF shelf, BC loop, and KAc regions allowed us to significantly increase potency and selectivity, resulting in the identification of non-CNS penetrant 19 (GNE-781, TR-FRET IC50 = 0.94 nM, BRET IC50 = 6.2 nM; BRD4(1) IC50 = 5100 nΜ) that maintained good in vivo PK properties in multiple species. Compound 19 displays antitumor activity in an AML tumor model and was also shown to decrease Foxp3 transcript levels in a dose dependent manner.


Subject(s)
Antineoplastic Agents/pharmacology , CREB-Binding Protein/antagonists & inhibitors , Pyrazoles/pharmacology , Pyridines/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , CREB-Binding Protein/chemistry , Dogs , Female , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , HEK293 Cells , Humans , Macaca fascicularis , Male , Mice , Protein Domains , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins c-myc/metabolism , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyrazoles/pharmacokinetics , Pyridines/chemical synthesis , Pyridines/chemistry , Pyridines/pharmacokinetics , RNA/genetics , Rats, Sprague-Dawley , Structure-Activity Relationship , Xenograft Model Antitumor Assays
6.
Pharmacol Res ; 126: 66-76, 2017 Dec.
Article in English | MEDLINE | ID: mdl-28392461

ABSTRACT

Overexpression of EGFR and MMP-2 plays an essential role in the initiation and progression of non-small-cell lung carcinoma (NSCLC). In this study, a novel format of EGFR/MMP-2 bi-targeted fusion protein Ec-LDP-TIMP2 and its enediyne-integrated analogue Ec-LDP(AE)-TIMP2 have been prepared by genetic engineering and molecular reconstitution. The Ec-LDP(AE)-TIMP2 comprises endogenous inhibitor of matrix metalloproteinase 2 (TIMP2), EGF-derived oligopeptide (Ec), lidamycin apoprotein (LDP), and the extremely potent cytotoxic enediyne (AE). By tissue microarray, Ec-LDP-TIMP2 showed high binding intensity and selectivity to human NSCLC specimens as compared with the matched non-cancerous tissues. By in vivo imaging, Ec-LDP-TIMP2 displayed prominent tumor-specific distribution in human NSCLC H460 xenograft. Particularly, Ec-LDP(AE)-TIMP2 inhibited tumor growth of H460 xenograft in athymic mice more striking. At doses of 0.2 and 0.4mg/kg, Ec-LDP(AE)-TIMP2 suppressed tumor growth by 74% and 89%, respectively. No histopathological changes were found in various organs of treated animals, suggesting that the effective dosage was tolerated. In summary, the ligand-based and enediyne-integrated fusion protein displaying extremely potent cytotoxicity might be highly effective for NSCLC therapy and useful as a carrier for drug delivery.


Subject(s)
Antineoplastic Agents/pharmacology , Carcinoma, Non-Small-Cell Lung/drug therapy , ErbB Receptors/antagonists & inhibitors , Lung Neoplasms/drug therapy , Matrix Metalloproteinase 2/metabolism , Recombinant Fusion Proteins/pharmacology , Tissue Inhibitor of Metalloproteinase-2/pharmacology , A549 Cells , Animals , Carcinoma, Non-Small-Cell Lung/metabolism , Cell Line, Tumor , Female , Humans , Ligands , Lung Neoplasms/metabolism , Matrix Metalloproteinase Inhibitors/pharmacology , Mice , Mice, Inbred BALB C , Mice, Nude , Oligopeptides/pharmacology , Xenograft Model Antitumor Assays/methods
7.
Oncotarget ; 8(9): 14748-14758, 2017 Feb 28.
Article in English | MEDLINE | ID: mdl-28107195

ABSTRACT

Previous studies have shown that intensive macropinocytosis occurs in cancer cells and neutral red (NR) is noted for its capability to enter into the cell massively through a process mimetic to macropinocytosis. In addition, trans-cinnamic acid (tCA) has been found to be an inhibitor of histone deacetylase (HDAC). In the present study, cinnamoylphenazine (CA-PZ) that consists of NR and tCA moieties was synthesized and evaluated. As shown, CA-PZ massively entered into colon carcinoma HT-29 cells and pancreatic carcinoma MIA PaCa-2 cells and this entry was blocked by 5-(N-ethyl-N-isopropyl) amiloride (EIPA, an inhibitor of macropinocytosis), indicating a macropinocytosis-mediated uptake. Furthermore, CA-PZ markedly increased the protein expression levels of acetyl-H3, acetyl-H4 and p21 in HT-29 cells and MIA PaCa-2 cells. CA-PZ significantly inhibited the growth of colon carcinoma HT-29 and pancreatic carcinoma MIA PaCa-2 xenografts. By in vivo imaging, CA-PZ displayed prominent accumulation in the tumor xenografts. The study indicates that the newly synthesized CA-PZ acts as an HDAC inhibitor in association with intensive macropinocytosis-mediated intracellular delivery in cancer cells. The use of neutral red for preparation of chimeric molecules with the attribute of macropinocytosis-mediated intracellular delivery might open an alternative way for development of HDAC inhibitors.


Subject(s)
Cinnamates/pharmacology , Colonic Neoplasms/drug therapy , Histone Deacetylase Inhibitors/pharmacology , Pancreatic Neoplasms/drug therapy , Phenazines/pharmacology , Pinocytosis/drug effects , Xenograft Model Antitumor Assays , A549 Cells , Amiloride/analogs & derivatives , Amiloride/pharmacology , Animals , Blotting, Western , Cell Line, Tumor , Cinnamates/chemical synthesis , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Epithelial Sodium Channel Blockers/pharmacology , Female , HCT116 Cells , HT29 Cells , Histone Deacetylase Inhibitors/chemical synthesis , Humans , Mice, Inbred BALB C , Mice, Nude , Microscopy, Confocal , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Phenazines/chemical synthesis
8.
Mol Med Rep ; 13(5): 4159-66, 2016 May.
Article in English | MEDLINE | ID: mdl-27035417

ABSTRACT

Previous studies have shown that trans-cinnamic acid (tCA) has a broad spectrum of biological activities, and exhibits antioxidant, anti-inflammatory and anticancer properties. In addition, tCA and a variety of its analogs have been detected as gut microbe­derived metabolites exerting various biological effects in the colon. The aim of this study was to assess the antitumor activity of tCA in vitro and in vivo, in particular its therapeutic efficacy against colon cancer xenografts in athymic mice. Furthermore, it aimed to examine the effects of tCA on histone deacetylases (HDACs) and to identify the underlying molecular mechanisms. Using an MTT assay, tCA was observed to inhibit the proliferation of several cancer cell lines, and the half maximal inhibitory concentration (IC50) in HT29 colon carcinoma cells was ~1 mM. Western blot analysis demonstrated that tCA upregulated the expression of acetyl­H3 and acetyl­H4 proteins, which was consistent with the effects of the HDAC inhibitor, trichostatin A (TSA). Furthermore, expression of Bcl­2 (a marker of cell proliferation) was reduced, and apoptosis was induced. Apoptosis was shown by the activation of cleavage of poly ADP ribose polymerase and the increased expression of Bax. Apoptosis was also confirmed using APC Annexin V and SYTOX Green Nucleic Acid Stain. In addition, the tCA­induced inhibition of the expression of HDAC markers and activation of apoptosis in tumor tissues were further confirmed by immunohistochemistry. Intragastric administration of tCA at doses of 1.0 and 1.5 mmol/kg body weight suppressed the growth of HT29 human colon carcinoma xenografts in athymic mice at well­tolerated doses. No toxic changes were found in the heart, lung, liver, kidney, colon or bone marrow following histopathological examination. This study indicated that tCA is effective against colon cancer xenograft in nude mice. The antitumor mechanism of tCA was mediated, at least in part, by inhibition of HDACs in cancer cells. As an endogenous microbial metabolite predominantly produced in the colon, tCA is an agent of interest for further evaluation.


Subject(s)
Antineoplastic Agents/pharmacology , Cinnamates/pharmacology , Colonic Neoplasms/drug therapy , Histone Deacetylase Inhibitors/pharmacology , Animals , Apoptosis/drug effects , Cell Line, Tumor , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Proto-Oncogene Proteins c-bcl-2/biosynthesis , Xenograft Model Antitumor Assays
10.
J Med Chem ; 56(11): 4521-36, 2013 Jun 13.
Article in English | MEDLINE | ID: mdl-23668484

ABSTRACT

Herein we report our lead optimization effort to identify potent, selective, and orally bioavailable TYK2 inhibitors, starting with lead molecule 3. We used structure-based design to discover 2,6-dichloro-4-cyanophenyl and (1R,2R)-2-fluorocyclopropylamide modifications, each of which exhibited improved TYK2 potency and JAK1 and JAK2 selectivity relative to 3. Further optimization eventually led to compound 37 that showed good TYK2 enzyme and interleukin-12 (IL-12) cell potency, as well as acceptable cellular JAK1 and JAK2 selectivity and excellent oral exposure in mice. When tested in a mouse IL-12 PK/PD model, compound 37 showed statistically significant knockdown of cytokine interferon-γ (IFNγ), suggesting that selective inhibition of TYK2 kinase activity might be sufficient to block the IL-12 pathway in vivo.


Subject(s)
4-Aminopyridine/analogs & derivatives , 4-Aminopyridine/chemical synthesis , Aminopyridines/chemical synthesis , Benzamides/chemical synthesis , TYK2 Kinase/antagonists & inhibitors , 4-Aminopyridine/pharmacokinetics , 4-Aminopyridine/pharmacology , Administration, Oral , Aminopyridines/pharmacokinetics , Aminopyridines/pharmacology , Animals , Benzamides/pharmacokinetics , Benzamides/pharmacology , Biological Availability , Crystallography, X-Ray , Interferon-gamma/antagonists & inhibitors , Interferon-gamma/biosynthesis , Interleukin-12/metabolism , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 2/antagonists & inhibitors , Janus Kinase 3/antagonists & inhibitors , Mice , Microsomes, Liver/metabolism , Models, Molecular , Protein Binding , Rats , STAT4 Transcription Factor/antagonists & inhibitors , Stereoisomerism , Structure-Activity Relationship
11.
J Med Chem ; 54(22): 7815-33, 2011 Nov 24.
Article in English | MEDLINE | ID: mdl-21985639

ABSTRACT

Of the four class I phosphoinositide 3-kinase (PI3K) isoforms, PI3Kα has justly received the most attention for its potential in cancer therapy. Herein we report our successful approaches to achieve PI3Kα vs PI3Kß selectivity for two chemical series. In the thienopyrimidine series of inhibitors, we propose that select ligands achieve selectivity derived from a hydrogen bonding interaction with Arg770 of PI3Kα that is not attained with the corresponding Lys777 of PI3Kß. In the benzoxepin series of inhibitors, the selectivity observed can be rationalized by the difference in electrostatic potential between the two isoforms in a given region rather than any specific interaction.


Subject(s)
Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Models, Molecular , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Benzoxepins/chemistry , Benzoxepins/pharmacokinetics , Benzoxepins/pharmacology , Cell Line, Tumor , Class I Phosphatidylinositol 3-Kinases/chemistry , Crystallography, X-Ray , Drug Design , Drug Screening Assays, Antitumor , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Humans , Hydrogen Bonding , Isoenzymes/antagonists & inhibitors , Isoenzymes/chemistry , Mice , Piperazines/chemistry , Piperazines/pharmacokinetics , Piperazines/pharmacology , Protein Conformation , Pyrimidines/chemistry , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Rats , Structure-Activity Relationship
12.
J Med Chem ; 54(21): 7579-87, 2011 Nov 10.
Article in English | MEDLINE | ID: mdl-21981714

ABSTRACT

The discovery of 2 (GDC-0980), a class I PI3K and mTOR kinase inhibitor for oncology indications, is described. mTOR inhibition was added to the class I PI3K inhibitor 1 (GDC-0941) scaffold primarily through the substitution of the indazole in 1 for a 2-aminopyrimidine. This substitution also increased the microsomal stability and the free fraction of compounds as evidenced through a pairwise comparison of molecules that were otherwise identical. Highlighted in detail are analogues of an advanced compound 4 that were designed to improve solubility, resulting in 2. This compound, is potent across PI3K class I isoforms with IC(50)s of 5, 27, 7, and 14 nM for PI3Kα, ß, δ, and γ, respectively, inhibits mTOR with a K(i) of 17 nM yet is highly selective versus a large panel of kinases including others in the PIKK family. On the basis of the cell potency, low clearance in mouse, and high free fraction, 2 demonstrated significant efficacy in mouse xenografts when dosed as low as 1 mg/kg orally and is currently in phase I clinical trials for cancer.


Subject(s)
Antineoplastic Agents/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Pyrimidines/chemical synthesis , TOR Serine-Threonine Kinases/antagonists & inhibitors , Administration, Oral , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Cell Line, Tumor , Crystallography, X-Ray , Drug Screening Assays, Antitumor , Humans , In Vitro Techniques , Isoenzymes/antagonists & inhibitors , Mice , Mice, Nude , Microsomes, Liver/metabolism , Models, Molecular , Neoplasm Transplantation , Protein Conformation , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Rats , Stereoisomerism , Structure-Activity Relationship , Transplantation, Heterologous
14.
Bioorg Med Chem Lett ; 20(20): 6048-51, 2010 Oct 15.
Article in English | MEDLINE | ID: mdl-20822905

ABSTRACT

Starting from HTS hit 1a, X-ray co-crystallization and molecular modeling were used to design potent and selective inhibitors of PI3-kinase. Bioavailablity in this series was improved through careful modulation of physicochemical properties. Compound 12 displayed in vivo knockdown of PI3K pharmacodynamic markers such as pAKT, pPRAS40, and pS6RP in a PC3 prostate cancer xenograft model.


Subject(s)
Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Animals , Cell Line , Crystallography, X-Ray , Humans , Male , Mice , Models, Molecular , Phosphatidylinositol 3-Kinases/chemistry , Phosphatidylinositol 3-Kinases/metabolism , Prostatic Neoplasms/enzymology , Protein Kinase Inhibitors/pharmacokinetics , Pyrazoles/chemistry , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Pyridines/pharmacokinetics , Pyrimidines/pharmacokinetics , Rats , Solubility , Structure-Activity Relationship
15.
Bioorg Med Chem Lett ; 20(8): 2408-11, 2010 Apr 15.
Article in English | MEDLINE | ID: mdl-20346656

ABSTRACT

Efforts to identify potent small molecule inhibitors of PI3 kinase and mTOR led to the discovery of the exceptionally potent 6-aryl morpholino thienopyrimidine 6. In an effort to reduce the melting point in analogs of 6, the thienopyrimidine was modified by the addition of a methyl group to disrupt planarity. This modification resulted in a general improvement in in vivo clearance. This discovery led to the identification of GNE-477 (8), a potent and efficacious dual PI3K/mTOR inhibitor.


Subject(s)
Enzyme Inhibitors/pharmacology , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Phosphoinositide-3 Kinase Inhibitors , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrimidines/pharmacology , Thiophenes/pharmacology , Animals , Dogs , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Female , Mice , Pyrimidines/chemistry , Rats , TOR Serine-Threonine Kinases , Thiophenes/chemistry
16.
J Med Chem ; 53(3): 1086-97, 2010 Feb 11.
Article in English | MEDLINE | ID: mdl-20050669

ABSTRACT

The PI3K/AKT/mTOR pathway has been shown to play an important role in cancer. Starting with compounds 1 and 2 (GDC-0941) as templates, (thienopyrimidin-2-yl)aminopyrimidines were discovered as potent inhibitors of PI3K or both PI3K and mTOR. Structural information derived from PI3K gamma-ligand cocrystal structures of 1 and 2 were used to design inhibitors that maintained potency for PI3K yet improved metabolic stability and oral bioavailability relative to 1. The addition of a single methyl group to the optimized 5 resulted in 21, which had significantly reduced potency for mTOR. The lead compounds 5 (GNE-493) and 21 (GNE-490) have good pharmacokinetic (PK) parameters, are highly selective, demonstrate knock down of pathway markers in vivo, and are efficacious in xenograft models where the PI3K pathway is deregulated. Both compounds were compared in a PI3K alpha mutated MCF7.1 xenograft model and were found to have equivalent efficacy when normalized for exposure.


Subject(s)
Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrimidines/pharmacology , Thiophenes/pharmacology , Administration, Oral , Animals , Cell Proliferation/drug effects , Class Ib Phosphatidylinositol 3-Kinase , Isoenzymes/antagonists & inhibitors , Mice , Mice, Nude , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Structure-Activity Relationship , TOR Serine-Threonine Kinases , Thiophenes/chemical synthesis , Thiophenes/chemistry , Xenograft Model Antitumor Assays
17.
Chem Pharm Bull (Tokyo) ; 57(9): 1004-7, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19721266

ABSTRACT

Based upon the biphenyl 1-(2-naphthyl)-1H-pyrazole-5-carboxylamides reported in our previous communications, we designed and discovered 2-(6-chloro-3-methylsulfonyl)-naphthyl as an optimal factor Xa S1 binding element. Employing a key Diels-Alder reaction of 1,4-dihydro-2,3-benzoxathiin-3-oxide with maleic anhydride and a key Cu(I)-mediated methylsulfonylation, we prepared two biphenyl 1-(2-(6-chloro-3-methylsulfonyl)-naphthyl)-1H-pyrazole-5-carboxylamides as highly potent factor Xa inhibitors with K(i) values of 0.065 nM and 0.045 nM respectively, and demonstrated the synergistically enhanced binding interaction in the factor Xa S1 site.


Subject(s)
Amides/chemical synthesis , Factor Xa Inhibitors , Serine Proteinase Inhibitors/chemical synthesis , Amides/chemistry , Amides/pharmacology , Binding Sites , Drug Design , Factor Xa/metabolism , Protein Binding , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology
18.
J Med Chem ; 52(10): 3300-7, 2009 May 28.
Article in English | MEDLINE | ID: mdl-19402633

ABSTRACT

The two major Aurora kinases carry out critical functions at distinct mitotic stages. Selective inhibitors of these kinases, as well as pan-Aurora inhibitors, show antitumor efficacy and are now under clinical investigation. However, the ATP-binding sites of Aurora A and Aurora B are virtually identical, and the structural basis for selective inhibition has therefore not been clear. We report here a class of bisanilinopyrimidine Aurora A inhibitors with excellent selectivity for Aurora A over Aurora B, both in enzymatic assays and in cellular phenotypic assays. Crystal structures of two of the inhibitors in complex with Aurora A implicate a single amino acid difference in Aurora B as responsible for poor inhibitory activity against this enzyme. Mutation of this residue in Aurora B (E161T) or Aurora A (T217E) is sufficient to swap the inhibition profile, suggesting that this difference might be exploited more generally to achieve high selectivity for Aurora A.


Subject(s)
Antineoplastic Agents/chemistry , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrimidines/chemistry , Antineoplastic Agents/pharmacology , Aurora Kinase B , Aurora Kinases , Cell Line, Tumor , Crystallography, X-Ray , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Molecular Structure , Protein Conformation , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/chemistry , Protein Serine-Threonine Kinases/genetics , Pyrimidines/pharmacology , Structure-Activity Relationship
19.
Bioorg Med Chem Lett ; 19(8): 2179-85, 2009 Apr 15.
Article in English | MEDLINE | ID: mdl-19297154

ABSTRACT

Systematic SAR studies of in vitro factor Xa inhibitory activity around compound 1 were performed by modifying each of the three phenyl rings. A class of highly potent, selective, efficacious and orally bioavailable direct factor Xa inhibitors was discovered. These compounds were screened in hERG binding assays to examine the effects of substitution groups on the hERG channel affinity. From the leading compounds, betrixaban (compound 11, PRT054021) has been selected as the clinical candidate for development.


Subject(s)
Anticoagulants/chemical synthesis , Anticoagulants/pharmacology , Benzamides/chemical synthesis , Benzamides/pharmacology , Drug Discovery/methods , Factor Xa Inhibitors , Pyridines/chemical synthesis , Pyridines/pharmacology , Administration, Oral , Animals , Anticoagulants/administration & dosage , Benzamides/administration & dosage , Catalytic Domain/drug effects , Cell Line , Dogs , Dose-Response Relationship, Drug , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/genetics , Factor Xa/metabolism , Humans , Macaca fascicularis , Pyridines/administration & dosage , Rabbits , Rats
20.
Bioorg Med Chem Lett ; 19(8): 2186-9, 2009 Apr 15.
Article in English | MEDLINE | ID: mdl-19297158

ABSTRACT

Anthranilamide-based benzamidine compound 4 and its N-substituted analogs were designed and examined as factor Xa inhibitors using substituted benzamidines as unconventional S4 binding element. A group of N,N-dialkylbenzamidines (11, 17 and 24) have been discovered as potent factor Xa inhibitors with strong anticoagulant activity and promising oral PK profiles.


Subject(s)
Anticoagulants/administration & dosage , Anticoagulants/chemical synthesis , Benzamidines/administration & dosage , Benzamidines/chemical synthesis , Factor Xa Inhibitors , ortho-Aminobenzoates/administration & dosage , ortho-Aminobenzoates/chemical synthesis , Administration, Oral , Animals , Anticoagulants/pharmacokinetics , Benzamidines/pharmacokinetics , Biological Availability , Dogs , Factor Xa/pharmacokinetics , Humans , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , ortho-Aminobenzoates/pharmacokinetics
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