- Discovery of novel selective Janus kinase 2 (JAK2) inhibitors bearing a 1H-pyrazolo[3,4-d]pyrimidin-4-amino scaffold
-
Janus kinases (JAKs) regulate various cancers and immune responses and are targets for the treatment of cancers and immune diseases. A new series of 1H-pyrazolo[3,4-d]pyrimidin-4-amino derivatives were synthesized and optimized by introducing a functional 3,5-disubstituted-1H-pyrazole moiety into the C-3 moiety of pyrazole template, and then were biologically evaluated as potent Janus kinase 2 (JAK2) inhibitors. Among these molecules, inhibitors 11f, 11g, 11h and 11k displayed strong activity and selectivity against the JAK2 kinase, with IC50 values of 7.2 nM, 6.5 nM, 8.0 nM and 9.7 nM, respectively. In particular, the cellular inhibitory assay and western blot analysis further support the JAK2 selectivity of compound 11g also in cells. Furthermore, compound 11g also exhibited potent inhibitory activity in lymphocytes proliferation assay and delayed hypersensitivity assay. Taken together, the novel JAK2 selective inhibitors discovered in this study may be potential lead compounds for new drug discovery via further development of more potent and selective JAK2 inhibitors.
- Yin, Yuan,Chen, Cheng-Juan,Yu, Ru-Nan,Shu, Lei,Zhang, Tian-Tai,Zhang, Da-Yong
-
p. 1562 - 1576
(2019/03/06)
-
- NEW COMPOUND HAVING FGFR INHIBITORY ACTIVITY AND PREPARATION AND APPLICATION THEREOF
-
The present invention relates to a new compound having an FGFR inhibitory activity and preparation and application thereof. In particular, the compound according to the present invention has a structure as shown in formula I, wherein each group and substituent are as defined in the description. Also disclosed in the present invention are a preparation method for the compound and a use thereof in preparation of a drug for treating and/or preventing a tumor-related disease and/or an FGFR-related disease.
- -
-
Paragraph 0137; 0138
(2019/05/30)
-
- Structure-based design and synthesis of 1H-pyrazolo[3,4-d]pyrimidin-4-amino derivatives as Janus kinase 3 inhibitors
-
Janus kinases (JAKs) regulate various inflammatory and immune responses and are targets for the treatment of inflammatory and immune diseases. Here we report the discovery and optimization of 1H-pyrazolo[3,4-d]pyrimidin-4-amino as covalent JAK3 inhibitors that exploit a unique cysteine (Cys909) residue in JAK3. Our optimization study gave compound 12a, which exhibited potent JAK3 inhibitory activity (IC50 of 6.2 nM) as well as excellent JAK kinase selectivity (>60-fold). In cellular assay, 12a exhibited potent immunomodulating effect on IL-2-stimulated T cell proliferation (IC50 of 9.4 μM). Further, compound 12a showed efficacy in delayed hypersensitivity assay. The data supports the further investigation of these compounds as novel JAKs inhibitors.
- Yin, Yuan,Chen, Cheng-Juan,Yu, Ru-Nan,Wang, Zhi-Jian,Zhang, Tian-Tai,Zhang, Da-Yong
-
p. 4774 - 4786
(2018/08/24)
-
- Inhibition of Calcium Dependent Protein Kinase 1 (CDPK1) by Pyrazolopyrimidine Analogs Decreases Establishment and Reoccurrence of Central Nervous System Disease by Toxoplasma gondii
-
Calcium dependent protein kinase 1 (CDPK1) is an essential enzyme in the opportunistic pathogen Toxoplasma gondii. CDPK1 controls multiple processes that are critical to the intracellular replicative cycle of T. gondii including secretion of adhesins, motility, invasion, and egress. Remarkably, CDPK1 contains a small glycine gatekeeper residue in the ATP binding pocket making it sensitive to ATP-competitive inhibitors with bulky substituents that complement this expanded binding pocket. Here we explored structure-activity relationships of a series of pyrazolopyrimidine inhibitors of CDPK1 with the goal of increasing selectivity over host enzymes, improving antiparasite potency, and improving metabolic stability. The resulting lead compound 24 exhibited excellent enzyme inhibition and selectivity for CDPK1 and potently inhibited parasite growth in vitro. Compound 24 was also effective at treating acute toxoplasmosis in the mouse, reducing dissemination to the central nervous system, and decreasing reactivation of chronic infection in severely immunocompromised mice. These findings provide proof of concept for the development of small molecule inhibitors of CDPK1 for treatment of CNS toxoplasmosis.
- Rutaganira, Florentine U.,Barks, Jennifer,Dhason, Mary Savari,Wang, Qiuling,Lopez, Michael S.,Long, Shaojun,Radke, Joshua B.,Jones, Nathaniel G.,Maddirala, Amarendar R.,Janetka, James W.,El Bakkouri, Majida,Hui, Raymond,Shokat, Kevan M.,Sibley, L. David
-
supporting information
p. 9976 - 9989
(2018/01/11)
-
- CYCLIC DI-NUCLEOTIDE COMPOUNDS AND METHODS OF USE
-
Disclosed are cyclic-di-nucleotide cGAMP analogs, methods of synthesizing the compounds, pharmaceutical compositions comprising the compounds thereof, and use of compounds and compositions in medical therapy.
- -
-
-
- Rapid Discovery and Structure-Activity Relationships of Pyrazolopyrimidines That Potently Suppress Breast Cancer Cell Growth via SRC Kinase Inhibition with Exceptional Selectivity over ABL Kinase
-
Novel pyrazolopyrimidines displaying high potency and selectivity toward SRC family kinases have been developed by combining ligand-based design and phenotypic screening in an iterative manner. Compounds were derived from the promiscuous kinase inhibitor PP1 to search for analogs that could potentially target a broad spectrum of kinases involved in cancer. Phenotypic screening against MCF7 mammary adenocarcinoma cells generated target-agnostic structure-activity relationships that biased subsequent designs toward breast cancer treatment rather than to a particular target. This strategy led to the discovery of two potent antiproliferative leads with phenotypically distinct anticancer mode of actions. Kinase profiling and further optimization resulted in eCF506, the first small molecule with subnanomolar IC50 for SRC that requires 3 orders of magnitude greater concentration to inhibit ABL. eCF506 exhibits excellent water solubility, an optimal DMPK profile and oral bioavailability, halts SRC-associated neuromast migration in zebrafish embryos without inducing life-threatening heart defects, and inhibits SRC phosphorylation in tumor xenografts in mice.
- Fraser, Craig,Dawson, John C.,Dowling, Reece,Houston, Douglas R.,Weiss, Jason T.,Munro, Alison F.,Muir, Morwenna,Harrington, Lea,Webster, Scott P.,Frame, Margaret C.,Brunton, Valerie G.,Patton, E. Elizabeth,Carragher, Neil O.,Unciti-Broceta, Asier
-
supporting information
p. 4697 - 4710
(2016/06/13)
-
- COMPOUNDS
-
A first aspect of the- invention relates to a compound of formula (I), or a pharmaceutically acceptable salt or ester thereof, (Formula (I)) wherein: R1 is (CH2)mNR11R12;R2 is selected from H, halo, OR13, ΝΗR13, alkyl, alkenyl and alkynyl; R3 is selected from alkyl, alkenyl, alkynyl, aryl, halo, aryloxy, NHCO2R4, NHCONR5R6, NHCOR7, NH-alkyl, NH-alkenyl, NH(CH2);n-aryl, (CH2)p-heteroaryl, (CH2)qCO2R8, (CH2)rCOR9 and NHSO2R10, wherein each alkyl, alkenyl, aryl or heteroaryl moiety in the aforementioned list is optionally further substituted by one or more groups selected from alkyl, halo OH, NH2, alkoxy, aryloxy, alkylamino, arylamino, carboxyl and carboxamide; R4 to R10 and R13 are each independently selected from alkyl, alkenyl and aryl; R11 and R12 are each independently selected from alkyl and alkenyl; or R11 and R:12 are linked together with the nitrogen to which they are attached to form a heterocycloalkyl or heterocycloalkenyl group; n, m, p, q and r are each independently selected from 0, 1, 2,.3. 4, 5 and 6. Further aspects relate to pharmaceutical compositions, therapeutic uses and process for preparing according to the invention.
- -
-
Page/Page column 47; 48
(2016/12/07)
-
- MTOR MODULATORS AND USES THEREOF
-
The present invention provides methods and compositions for selective modulation of certain protein kinases, and especially mTor complexes. The methods and compositions are particularly useful in inhibiting mTor selectively for therapeutic applications.
- -
-
Paragraph 0320; 0321
(2016/01/30)
-
- Discovery of Pyrazolopyrimidine Derivatives as Novel Dual Inhibitors of BTK and PI3Kδ
-
The aberrant activation of B-cells has been implicated in several types of cancers and hematological disorders. BTK and PI3Kδ are kinases responsible for B-cell signal transduction, and inhibitors of these enzymes have demonstrated clinical benefit in certain types of lymphoma. Simultaneous inhibition of these pathways could result in more robust responses or overcome resistance as observed in single agent use. We report a series of novel compounds that have low nanomolar potency against both BTK and PI3Kδ as well as acceptable PK properties that could be useful in the development of treatments against B-cell related diseases.
- Pujala, Brahmam,Agarwal, Anil K.,Middya, Sandip,Banerjee, Monali,Surya, Arjun,Nayak, Anjan K.,Gupta, Ashu,Khare, Sweta,Guguloth, Rambabu,Randive, Nitin A.,Shinde, Bharat U.,Thakur, Anamika,Patel, Dhananjay I.,Raja, Mohd.,Green, Michael J.,Alfaro, Jennifer,Avila, Patricio,Pérez de Arce, Felipe,Almirez, Ramona G.,Kanno, Stacy,Bernales, Sebastián,Hung, David T.,Chakravarty, Sarvajit,McCullagh, Emma,Quinn, Kevin P.,Rai, Roopa,Pham, Son M.
-
supporting information
p. 1161 - 1166
(2016/12/16)
-
- A PROCESS FOR THE PREPARATION OF IBRUTINIB
-
The present invention provides processes for the preparation of ibrutinib, intermediate compounds of Formula VI and Formula VIII, and salts thereof. The processes of the present invention are commercially viable, cost-effective, environmentally friendly, and make use of inexpensive, non-hazardous, safe chemicals that are easy to handle.
- -
-
Page/Page column 24
(2016/06/15)
-
- PROCESS FOR THE PREPARATION OF IBRUTINIB
-
A processes for the preparation of 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4- d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one (ibrutinib). The disclosed process may be useful for preparing ibrutinib that may be included in pharmaceutical dosage forms.
- -
-
Page/Page column 21; 22
(2017/01/02)
-
- Bruton tyrosine kinases inhibitor
-
The invention relates to pyrazolo[3,4-d]pyrimidine derivatives, and a preparation method and application thereof to medicines. Concretely, the invention relates to new pyrazolo[3,4-d]pyrimidine derivatives shown as general formulas I and IA, a preparation method of the derivatives, a pharmaceutical composition containing the derivatives, and application of the derivatives as therapy equipment especially as a Bruton tyrosine kinases inhibitor.
- -
-
Paragraph 0105; 0106; 0107; 0108
(2016/10/08)
-
- Preparation method for ibrutinib
-
The invention discloses a preparation method for ibrutinib and belongs to the technical field of drug synthesis. The preparation method specifically includes the steps that 3-amino-4-cyano pyrazol and formamidine acetate serve as initial raw materials, and ibrutinib is obtained through a cyclization reaction, a halogenating reaction, a nucleophilic substitution reaction, a Mitsunobu reaction and an amidation reaction. According to the method, the raw materials are easy to obtain, conditions are mild, the process operability and controllability are high, cost is low, the yield is high, fewer side products are generated, purification is easy, and the high-quality product is obtained.
- -
-
Paragraph 0070; 0071; 0072
(2016/10/10)
-
- INHIBITORS OF THE TEC KINASE ENZYME FAMILY
-
The present invention relates to a novel family of kinases inhibitors. Compounds of this class have been found to have inhibitory activity against members of the TEC kinase family, particularly BTK. The present invention is directed to a compound of Formula I or pharmaceutically acceptable salt, solvate, solvate of salt, stereoisomer, tautomer, isotope, prodrug, complex or biologically active metabolite thereof, for use in therapy.
- -
-
Page/Page column 51
(2016/12/22)
-
- Studies on the ATP Binding Site of Fyn Kinase for the Identification of New Inhibitors and Their Evaluation as Potential Agents against Tauopathies and Tumors
-
Fyn is a member of the Src-family of nonreceptor protein-tyrosine kinases. Its abnormal activity has been shown to be related to various human cancers as well as to severe pathologies, such as Alzheimer's and Parkinson's diseases. Herein, a structure-based drug design protocol was employed aimed at identifying novel Fyn inhibitors. Two hits from commercial sources (1, 2) were found active against Fyn with Ki of about 2 μM, while derivative 4a, derived from our internal library, showed a Ki of 0.9 μM. A hit-to-lead optimization effort was then initiated on derivative 4a to improve its potency. Slightly modifications rapidly determine an increase in the binding affinity, with the best inhibitors 4c and 4d having Kis of 70 and 95 nM, respectively. Both compounds were found able to inhibit the phosphorylation of the protein Tau in an Alzheimer's model cell line and showed antiproliferative activities against different cancer cell lines. (Chemical Equation Presented).
- Tintori, Cristina,La Sala, Giuseppina,Vignaroli, Giulia,Botta, Lorenzo,Fallacara, Anna Lucia,Falchi, Federico,Radi, Marco,Zamperini, Claudio,Dreassi, Elena,Dello Iacono, Lucia,Orioli, Donata,Biamonti, Giuseppe,Garbelli, Mirko,Lossani, Andrea,Gasparrini, Francesca,Tuccinardi, Tiziano,Laurenzana, Ilaria,Angelucci, Adriano,Maga, Giovanni,Schenone, Silvia,Brullo, Chiara,Musumeci, Francesca,Desogus, Andrea,Crespan, Emmanuele,Botta, Maurizio
-
p. 4590 - 4609
(2015/06/30)
-
- HETEROCYCLIC COMPOUNDS AND METHODS OF USE
-
The present application discloses compounds that are inhibitors of Btk, compounds that are inhibitors of ΡΒΚδ, and compounds that are dual inhibitors of both Btk and PI3Kδ. Also described are methods for synthesizing such inhibitors and methods for using such inhibitors for the treatment of diseases wherein inhibition of Btk and PI3Kδ provides a therapeutic benefit to a patient having the disease.
- -
-
Paragraph 0205; 0241; 0273
(2015/05/05)
-
- PYRAZOLO-, IMIDAZOLO- AND PYRROLO-PYRIDINE OR -PYRIMIDINE DERIVATIVES AS INHIBITORS O BRUTONS KINASE (BTK)
-
The present application discloses compounds that are inhibitors of Btk, compounds that are inhibitors of ΡI3Κδ, and compounds that are dual inhibitors of both Btk and PI3Kδ. Also described are methods for synthesizing such inhibitors and methods for using such inhibitors for the treatment of diseases wherein inhibition of Btk and PI3Kδ provides a therapeutic benefit to a patient having the disease.
- -
-
Paragraph 0190; 0208; 0216
(2015/05/26)
-
- Benzothiazole Kinase Inhibitors and Methods of Use
-
The present invention provides chemical entities or compounds and pharmaceutical compositions thereof that are capable of modulating lipid kinases such PI3 kinases, tryosine kinases and protein kinases such as mTOR. Also provided in the present invention are methods of using these compositions to modulate these kinases especially for therapeutic applications.
- -
-
Paragraph 0405
(2015/09/22)
-
- Preparation of 8-Aza-7-deazaaristeromycin and -neplanocin A and Their 5′-Homologs
-
The synthesis of new members of the aristeromycin and neplaoncin A families of carbocyclic nucleosides possessing the 1H-pyrazolo[3,4-d]pyrimidine ring is reported. For this purpose, an adapted route to 4-amino-1H-pyrazolo[3,4-d]pyrimidine is described.
- Wang, Haisheng,Zhang, Yan,Ye, Wei,Schneller, Stewart W.
-
p. 1132 - 1135
(2015/08/06)
-
- COMBINATION PHARMACEUTICAL COMPOSITIONS AND USES THEREOF
-
The present invention provides for methods and pharmaceutical compositions for treating proliferative disorders. In one aspect, the method comprises administration of two cell-cycle suppressors having a synergistic effect. In another aspect, two cell-cycle suppressors having a synergistic effect are provided in a pharmaceutical composition.
- -
-
Paragraph 0460
(2014/12/09)
-
- TREATMENT OF DRY EYE
-
The present disclosure provides a method of treating dry eye by inhibition of Bruton's tyrosine kinase (hereinafter "BTK") inhibitors, pharmaceutical formulations comprising the same, and processes for preparing such compounds.
- -
-
Page/Page column 49
(2014/02/16)
-
- KINASE INHIBITORS
-
Provided herein are kinase inhibiting compounds and methods of using the same.
- -
-
Paragraph 0427-0429
(2014/11/11)
-
- Tyrosine kinase inhibitors
-
The present disclosure provides compounds such as pyrazolpyrimidine compounds, and pharmaceutically acceptable salts thereof, that are tyrosine kinase inhibitors, in particular BLK, BMX, EGFR, HER2, HER4, ITK, TEC, BTK, and TXK and are therefore useful for the treatment of diseases treatable by inhibition of tyrosine kinases such as cancer and inflammatory diseases such as arthritis, and the like. Also provided are pharmaceutical compositions containing such compounds and pharmaceutically acceptable salts thereof and processes for preparing such compounds and pharmaceutically acceptable salts thereof.
- -
-
Page/Page column 200
(2014/03/26)
-
- REVERSIBLE COVALENT PYRROLO- OR PYRAZOLOPYRIMIDINES USEFUL FOR THE TREATMENT CANCER AND AUTOIMMUNE DISEASES
-
Oral pharmaceutical formulations comprising reversible covalent compounds having a Michael acceptor moiety, a process of their production, and use of these formulations for the treatment of diseases treatable by such compounds such as cancer and autoimmune diseases.
- -
-
Page/Page column 156
(2014/01/09)
-
- PYRAZOLOPYRIMIDINE DERIVATIVES AS TYROSINE KINASE INHIBITORS
-
The present disclosure provides compounds and pharmaceutically acceptable salts that are tyrosine kinase inhibitors, in particular BLK, BMX, EGFR, HER2, HER4, ITK, Jak3, TEC, Btk, and TXK and are therefore useful for the treatment of diseases treatable by inhibition of tyrosine kinases such as cancer and inflammatory diseases such as arthritis, and the like. Also provided are pharmaceutical compositions containing such compounds and pharmaceutically acceptable salts and processes for preparing such compounds and pharmaceutically acceptable salts.
- -
-
Page/Page column 76
(2012/12/13)
-
- TYROSINE KINASE INHIBITORS
-
The present disclosure provides compounds and pharmaceutically acceptable salts thereof that are tyrosine kinase inhibitors, in particular BLK, BMX, EGFR, HER2, HER4, ITK, TEC, BTK, and TXK and are therefore useful for the treatment of diseases treatable by inhibition of tyrosine kinases such as cancer and inflammatory diseases such as arthritis, and the like. Also provided are pharmaceutical compositions containing such compounds and pharmaceutically acceptable salts thereof and processes for preparing such compounds and pharmaceutically acceptable salts thereof.
- -
-
Page/Page column 165
(2012/12/13)
-
- PROTEIN KINASE INHIBITORS AND METHODS OF TREATMENT
-
The present invention relates to chemical compounds of formula (I) and methods for their use and preparation. In particular, the invention relates to substituted pyrazolo[3,4-d]pyrimidine based compounds which can be used in treating proliferative disorders, use of these compounds in methods of therapy and the manufacture of medicaments as well as compositions containing these compounds.
- -
-
Page/Page column 102
(2012/02/01)
-
- COMPOSITIONS AND METHODS FOR TREATING TOXOPLASMOSIS. CRYPTOSPORIDIOSIS AND OTHER APICOMPLEXAN PROTOZOAN RELATED DISEASES
-
Compositions and methods for the treatment of toxoplasmosis-, caused by the infectious eukaryotic parasite Toxoplasma gondii (T, gondii) and for the treatment of ciyptosporidiosis, caused by the infectious eukaryotic parasites Cryptosporidium parvum (C parvuai) and Cnγtosporidium homimus (C. hominus) are described. In particular, the present disclosure is directed to compositions and methods for inhibiting either T. gondii calcium dependent protein kinases (TgCDPKs) or C. parvum and C. hominus calcium dependent protein kinases (CpDPKS) using pyrazolopyriinidine and/or imidazo[l,5-a]pyraziαe inhibitors, of the formula.(I), wherein the variables X. Y, Z, L. R1. and R3 are defined herein.
- -
-
Page/Page column 98
(2011/08/21)
-
- Microwave-assisted synthesis of N1- and C3-substituted pyrazolo[3,4-d] pyrimidine libraries
-
The parallel synthesis of a library N1- and C3-substituted-pyrazolo[3,4-d] pyrimidines is described. The microwave-assisted approach involves the de novo generation of the heterocyclic scaffold, facile alkylation at N1 via either a Mitsunobu or a direct alkylation reaction and arylation at C3 via a Suzuki reaction.
- Todorovic, Nick,Awuah, Emelia,Shakya, Tushar,Wright, Gerard D.,Capretta, Alfredo
-
supporting information; experimental part
p. 5761 - 5763
(2011/12/03)
-
- KINASE INHIBITORS AND METHODS OF USE
-
The present invention provides chemical entities or compounds and pharmaceutical compositions thereof that are capable of modulating certain protein kinases such as mTor, tyrosine kinases, and/or lipid kinases such as PI3 kinase. Also provided in the present invention are methods of using these compositions to modulate activities of one or more of these kinases, especially for therapeutic applications.
- -
-
Page/Page column 78
(2010/04/03)
-
- BENZOXAZOLE KINASE INHIBITORS AND METHODS OF USE
-
The present invention provides chemical entities or compounds and pharmaceutical compositions thereof that are capable of modulating certain protein kinases such as mTor, tyrosine kinases, and/or lipid kinases such as PI3 kinase. Also provided in the present invention are methods of using these compositions to modulate activities of one or more of these kinases, especially for therapeutic applications.
- -
-
Page/Page column 128
(2010/05/14)
-
- MODULATION OF PROTEIN TRAFFICKING
-
Compounds and compositions are provided for treatment or amelioration of one or more disorders characterized by defects in protein trafficking. A method of treating a disorder characterized by impaired protein trafficking includes administering to a subject or contacting a cell with a compound of Formula I: [formula here] or pharmaceutically acceptable salts or derivatives thereof.
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-
Page/Page column 165-166
(2009/06/27)
-
- INHIBITION OF ALPHA-SYNUCLEIN TOXICITY
-
Compounds and compositions are provided for treatment or amelioration of one or more symptoms of α-synuclein toxicity, α-synuclein mediated diseases or diseases in which α-synuclein fibrils are a symptom or cause of the disease.
- -
-
Page/Page column 68-69
(2008/06/13)
-
- Kinase antagonists
-
The present invention provides novel compounds that are antagonists of PI3 kinase, PI3 kinase and tryosine kinase, PI3Kinase and mTOR, or PI3Kinase, mTOR and tryosine kinase.
- -
-
Page/Page column 12; 16
(2008/06/13)
-
- Novel, highly potent adenosine deaminase inhibitors containing the pyrazolo[3,4-d]pyrimidine ring system. Synthesis, structure-activity relationships, and molecular modeling studies
-
This study reports the synthesis of a number of 1- and 2-alkyl derivatives of the 4-aminopyrazolo[3,4-d]pyrimidine (APP) nucleus and their evaluation as inhibitors of ADA from bovine spleen. The 2-substituted aminopyrazolopyrimidines proved to be potent inhibitors, most of them exhibiting Ki values in the nanomolar/subnanomolar range. In this series the inhibitory activity is enhanced with the increase in length of the alkyl chain, reaching a maximum with the n-decyl substituent. Insertion of a 2′-hydroxy group in the ra-decyl chain gave 3k, whose (R)-isomer displayed the highest inhibitory potency of the series (Ki 0.053 nM), showing an activity 2 orders of magnitude higher than that of (+)-EHNA (Ki 1.14 nM), which was taken as the reference standard. Docking simulations of aminopyrazolopyrimidines into the ADA binding site were also performed, to rationalize the structure-activity relationships of this class of inhibitors.
- Da Settimo, Federico,Primofiore, Giampaolo,La Motta, Concettina,Taliani, Sabrina,Simorini, Francesca,Marini, Anna Maria,Mugnaini, Laura,Lavecchia, Antonio,Novellino, Ettore,Tuscano, Daniela,Martini, Claudia
-
p. 5162 - 5174
(2007/10/03)
-
- Pyrazolopyrimidines as therapeutic agents
-
The present invention is directed to pyrazolopyrimidine derivatives of formula (I) wherein the substituents are defined herein, which are useful as kinase inhibitors and as such are useful for affecting angiogenesis and diseases and conditions associated with angiogenesis.
- -
-
-
- Real-time linear detection probes: sensitive 5'-minor groove binder-containing probes for PCR analysis
-
Oligonucleotide probes/conjugates are provided along with method for their use in assays to monitor amplification wherein the signal produced does not rely on 5′ nuclease digestion.
- -
-
-
- Pyrazolo[3,4-d]pyrimidines containing an extended 3-substituent as potent inhibitors of Lck -- a selectivity insight.
-
A series of para-substituted 3-phenyl pyrazolopyrimidines was synthesized and evaluated as inhibitors of lck. The nature of the substitution affected enzyme selectivity and potency for lck, src, kdr, and tie-2. The para-phenoxyphenyl analogue 2 is an orally active lck inhibitor with a bioavailability of 69% and exhibits an extended duration of action in animal models of T cell inhibition.
- Burchat, Andrew F,Calderwood, David J,Friedman, Michael M,Hirst, Gavin C,Li, Biqin,Rafferty, Paul,Ritter, Kurt,Skinner, Barbara S
-
p. 1687 - 1690
(2007/10/03)
-
- Pyrazolopyrimidines as therapeutic agents
-
The present invention provides compounds of Formula I, including pharmaceutically acceptable salts and/or prodrugs thereof, where G, R2, and R3 are defined as described herein.
- -
-
-
- Gene therapy of cancer: activation of nucleoside prodrugs with e. colipurine nucleoside phosphorylase
-
During the last few years, many gene therapy strategies have been developed for various disease targets. The development of anticancer gene therapy strategies to selectively generate cytotoxic nucleoside or nucleotide analogs is an attractive goal. One such approach involves the delivery of herpes simplex virus thymidine kinase followed by the acyclic nucleoside analog ganciclovir. We have developed another gene therapy methodology for the treatment of cancer that has several significant attributes. Specifically, our approach involves the delivery of E. coli purine nucleoside phosphorylase, followed by treatment with a relatively non-toxic nucleoside prodrug that is cleaved by the enzyme to a toxic compound. .This presentation describes the concept, details our search for suitable prodrugs, and summarizes the current biological data. Copyright
- Secrist III, John A.
-
p. 745 - 757
(2007/10/03)
-
- REACTION OF 4-CYANO-5-AMINOPYRAZOLE AND 3,4-DICYANO-5-AMINOPYRAZOLE WITH DIMETHYLFORMAMIDE DIETHYLACETAL
-
The condensation of 4-cyano-5-aminopyrazole or 3,4-dicyano-5-aminopyrazole with dimethylformamide diethylacetal was studied.It was shown that, in addition to the formation of dimethylaminomethyleneamino derivatives, alkylation of the pyrazole ring occurs under severe conditions without a solvent.Only the corresponding formamidino derivatives are formed when the same reactions are carried out in methanol under milder conditions.The site of addition of an ethyl group to the pyrazole ring in the N-alkyl derivatives obtained was established by 13C NMR and PMR spectroscopy.The possibility of the synthesis of 4-amino- or 4-methylmercaptopyrazolopyrimidines by cyclization of the ortho position was demonstrated for the first time.
- Bulychev, Yu. N.,Korbukh, I. A.,Preobrazhenskaya, M. N.,Chernyshov, A. I.,Esipov, S. E.
-
p. 215 - 221
(2007/10/02)
-
- Preparation of 4,6-diamino-5-arylazopyrimidines and adenine compounds
-
The present invention relates to a novel and useful process for preparing 4,6-diamino-5-arylazopyrimidine from an arylazomalononitrile in the presence of ammonium chloride and formamide. If desired, the 4,6-diamino-5-arylazopyrimidine may then be hydrogenated to form 4,5,6-triaminopyrimidine which, when the hydrogenation is carried out in the presence of formic acid or its derivative, gives adenine.
- -
-
-