- Synthesis and structure-activity relationship (SAR) study of 4-azabenzoxazole analogues as H3 antagonists
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The synthesis and SAR of a novel series of 4-azabenzoxazole histamine H3 antagonists is described. Introduction of substituted phenyl, pyridyl and fused heterocyclic groups to the 6-position of the 4-azabenzoxazole core gave a series of compounds with good H3 antagonist activity in both ex vivo and in vivo assays.
- Shao, Ning,Aslanian, Robert,West Jr., Robert E.,Williams, Shirley M.,Wu, Ren-Long,Hwa, Joyce,Sondey, Christopher,Lachowicz, Jean,Palani, Anandan
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- Discovery of CA-4948, an Orally Bioavailable IRAK4 Inhibitor for Treatment of Hematologic Malignancies
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Small molecule potent IRAK4 inhibitors from a novel bicyclic heterocycle class were designed and synthesized based on hits identified from Aurigene's compound library. The advanced lead compound, CA-4948, demonstrated good cellular activity in ABC DLBCL and AML cell lines. Inhibition of TLR signaling leading to decreased IL-6 levels was also observed in whole blood assays. CA-4948 demonstrated moderate to high selectivity in a panel of 329 kinases as well as exhibited desirable ADME and PK profiles including good oral bioavailability in mice, rat, and dog and showed >90% tumor growth inhibition in relevant tumor models with excellent correlation with in vivo PD modulation. CA-4948 was well tolerated in toxicity studies in both mouse and dog at efficacious exposure. The overall profile of CA-4948 prompted us to select it as a clinical candidate for evaluation in patients with relapsed or refractory hematologic malignancies including non-Hodgkin lymphoma and acute myeloid leukemia.
- Gummadi, Venkateshwar Rao,Boruah, Anima,Ainan, Bharathi Raja,Vare, Brahma Reddy,Manda, Srinivas,Gondle, Hari Prakash,Kumar, Shiva Nagendra,Mukherjee, Subhendu,Gore, Suraj T.,Krishnamurthy, Narasimha Rao,Marappan, Sivapriya,Nayak, Shilpa S.,Nellore, Kavitha,Balasubramanian, Wesley Roy,Bhumireddy, Archana,Giri, Sanjeev,Gopinath, Sreevalsam,Samiulla, Dodheri S.,Daginakatte, Girish,Basavaraju, Aravind,Chelur, Shekar,Eswarappa, Rajesh,Belliappa, Charamanna,Subramanya, Hosahalli S.,Booher, Robert N.,Ramachandra, Murali,Samajdar, Susanta
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- Azabenzene chemistry. Part 2 . Methylation of 2,3-dihydrooxazolo[4,5-b]pyridin-2-thione
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Studies have been made on the reactions of 2,3-dihydrooxazolo[4,5-b]pyridin-2-thione and of its potassium and sodium salts with methylating agents under various conditions. 1999 KluwerAcademic/Plenum.
- Aliev,Levkovich,Kristallovich,Abdullaev,Kartsev
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- Tunable Amine-Reactive Electrophiles for Selective Profiling of Lysine
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Proteome profiling by activated esters identified >9000 ligandable lysines but they are limited as covalent inhibitors due to poor hydrolytic stability. Here we report our efforts to design and discover a new series of tunable amine-reactive electrophiles (TAREs) for selective and robust labeling of lysine. The major challenges in developing selective probes for lysine are the high nucleophilicity of cysteines and poor hydrolytic stability. Our work circumvents these challenges by a unique design of the TAREs that form stable adducts with lysine and on reaction with cysteine generate another reactive electrophiles for lysine. We highlight that TAREs exhibit substantially high hydrolytic stability as compared to the activated esters and are non-cytotoxic thus have the potential to act as covalent ligands. We applied these alternative TAREs for the intracellular labeling of proteins in different cell lines, and for the selective identification of lysines in the human proteome on a global scale.
- Backus, Keriann M.,Boatner, Lisa M.,Cao, Jian,Farhi, Jonathan,Houk, Kendall N.,Li, Linwei,Raj, Monika,Spangle, Jennifer,Tang, Kuei-Chien
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supporting information
(2021/12/22)
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- General Entry into o-,o′-Heteroatom-Linked N-(Hetero)aryl-Imidazole Motifs by Gold-Catalysed Formal [3+2]-Dipolar Cycloaddition
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A general redox-neutral approach into the o-,o′-heteroatom-linked N-(hetero)aryl-imidazole family of heteroaromatics has been developed. New types of heteroatom substituted carbimidoyl nitrenoids are efficiently realised from robust, bench-stable N-(heteroaryl)-pyridinium-N-aminides by formal gold-catalysed [3+2]-dipolar cycloadditions across ynamides. Broad structural variety and functional group tolerance allows rapid access into diverse functionalised scaffolds, as exemplified by the preparation of 8 different heteroaromatic cores. (Figure presented.).
- Garzón, Miguel,Arce, Elsa M.,Reddy, Raju Jannapu,Davies, Paul W.
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supporting information
p. 1837 - 1843
(2017/06/09)
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- BICYCLIC HETEROCYCLYL DERIVATES AS IRAK4 INHIBITORS
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The present invention provides bicyclic heterocyclyl kinase enzyme inhibitor compounds of formula (I), which are therapeutically useful as kinase inhibitors, particularly IRAK4 inhibitors, wherein A, Y, Z, X1, X2, R1, R3, ‘m’, ‘n’ and ‘p’ have the meanings given in the specification and pharmaceutically acceptable salt or stereoisomer thereof that are useful in the treatment and prevention of diseases or disorder, in particular their use in diseases or disorder mediated by kinase enzyme, particularly IRAK4 enzyme. The present invention also provides pharmaceutical composition comprising at least one of the compounds of compound of formula (I) together with a pharmaceutically acceptable carrier, diluent or excipient therefor.
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Paragraph 0207; 0208
(2016/12/16)
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- BICYCLIC HETEROCYCLYL DERIVATIVES AS IRAK4 INHIBITORS
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The present invention provides bicyclic heterocyclyl kinase enzyme inhibitor compounds of formula (I), which are therapeutically useful as kinase inhibitors, particularly IRAK4 inhibitors. wherein A, Y, Z, X1, X2, X3, R1, R3, 'm', 'n' and 'p' have the meanings given in the specification and pharmaceutically acceptable salt or stereoisomer thereof that are useful in the treatment and prevention of diseases or disorder, in particular their use in diseases or disorder mediated by kinase enzyme, particularly IRAK4 enzyme. The present invention also provides pharmaceutical composition comprising at least one of the compounds of compound of formula (I) together with a pharmaceutically acceptable carrier, diluent or excipient therefor.
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Page/Page column 36
(2015/07/23)
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- An easy and fast ultrasonic selective S-alkylation of hetaryl thiols at room temperature
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A series of 2-alkylthio derivatives of hetaryl thiols were synthesized by selective S-alkylation with alkyl halides (bromides and iodides) with ultrasonic irradiation at room temperature. The reaction was found to be generally applicable to hetaryl thiol derivatives with different substituents in the aromatic nucleus and various alkyl halides. The reaction gives high to excellent yields of products with high purity.
- Deligeorgiev, Todor,Kaloyanova, Stefka,Lesev, Nedyalko,Vaquero, Juan J.
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experimental part
p. 783 - 788
(2011/10/09)
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- New cyanine dyes as base surrogates in PNA: Forced intercalation probes (FIT-probes) for homogeneous SNP detection
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Forced intercalation probes (FIT-probes) are nucleic acid probes, in which an intercalator cyanine dye such as thiazole orange (TO) serves as a replacement of a canonical nucleobase. These probes signal hybridization by showing strong increases of fluorescence. TO in FIT-probes responds to adjacent base mismatches by attenuation of fluorescence intensities at conditions where both matched and mismatched target DNA are bound. The interesting features of TO labeled FIT-probes posed the question whether the forced intercalation concept can be extended to other cyanine dyes of the thiazole orange family. Herein, we present the synthesis of three asymmetrical cyanine dyes and their incorporation into PNA-conjugates by means of both divergent and linear solid-phase synthesis. Melting analysis revealed that the DNA affinity of PNA probes remained high irrespective of the replacement of a nucleobase by the cyanines YO (oxazole yellow), MO or JO. Of the three new tested dye-PNA-conjugates, the YO-containing PNA has properties useful for homogeneous SNP detection. YO-PNA is demonstrated to signal the presence of fully complementary DNA by up to 20-fold enhancement of fluorescence. In addition, YO emission discriminates against single base mismatches by attenuation of fluorescence. Oxazole yellow (YO) as a base surrogate in PNA may prove useful in the multiplex detection of single base mutations at non-stringent conditions.
- Bethge, Lucas,Jarikote, Dilip Venkatrao,Seitz, Oliver
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p. 114 - 125
(2008/04/05)
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- Benzothiazole, thiazolopyridine, benzooxazole and oxazolopyridine derivatives
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This invention is concerned with compounds of the formula wherein A, B1, B2, R1, R2 and G are as defined in the description and claims, and pharmaceutically acceptable salts thereof. The invention further relates to pharmaceutical compositions containing such compounds, to a process for their preparation and to their use for the treatment and/or prevention of diseases which are associated with the modulation of SST receptors subtype 5.
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Page/Page column 57
(2010/11/23)
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- AZABENZOXAZOLES FOR THE TREATMENT OF CNS DISORDERS
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The present invention relates to a7 nicotinic receptor agonists of formula (la) or (lb) as described herein and to a method for treating disorders of the Central Nervous System (CNS) and other disorders in a mammal, including a human, by administering to the mammal an a7 nicotinic receptor agonist of formula (la) or (lb). It also relates to pharmaceutical compositions containing a pharmaceutically acceptable carrier and a CNS-penetrant a7nicotinic receptor agonist of formula (la) or (lb).
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Page/Page column 45
(2010/11/30)
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- Non-imidazole histamine H3 ligands. Part III. New 4-n-propylpiperazines as non-imidazole histamine H3-antagonists
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In search for a new lead of non-imidazole histamine H3-receptor antagonists, a series of 1[(2-thiazolopyridine)-4-n-propyl]piperazines, the analogous 1-[(2-oxazolopyridine)-4-npropyl]piperazines, 1-[(2-benzothiazole)-4- n-propyl]piperazine and 1-[(2-benzooxazole)4-n-propyl]piperazine were prepared and in vitro tested as H3-receptor antagonists (the electrically evoked contraction of the guinea-pig jejunum). It appeared that by comparison of homologous pairs the thiazolo derivatives have slightly higher activity than their oxazolo analogues. The most potent compound of these series is the 1-(2-thiazolo[4,5-c]pyridine)-4-n-propylpiperazine (3c) with pA2 = 7.25 (its oxazole analogue (4g) showed pA2 = 6.9). The structure-activity relationships for compounds with various positions of the nitrogen in the benzene ring for the thiazoles compared with oxazoles are discussed.
- Walczyski, Krzysztof,Zuiderveld, Obbe P.,Timmerman, Henk
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- Method for optical measurement of multi-stranded nucleic acid using cyanine dyes
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A method for optical measurement of a multi-stranded nucleic acid which comprises the step of bringing a compound into contact with a multi-stranded nucleic acid wherein said compound is capable of interacting with the multi-stranded nucleic acid, wherein the compound has the following properties:(a) the compound can exist in a substantially colorless and non-fluorescent state under at least one condition in an aqueous solution in the absence of the multi-stranded nucleic acid, and(b) when the multi-stranded nucleic acid is allowed to exist in the condition defined in the above (a), the compound changes to a substantially colored state based on an interaction with the multi-stranded nucleic acid and substantially expresses fluorescent property based on said interaction.
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