- Demethylation of 4-methoxyphenylbutyric acid using molten pyridinium hydrochloride on multikilogram scale
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4-Methoxyphenylbutyric acid (2) is smoothly demethylated in 3 h at 180°C when melted with pyridinium hydrochloride (Pyr·HCl), affording 4-hydroxyphenylbutyric acid (3), a key starting material for the preclinical candidate LY518674 (1). The adaptation of
- Schmid, Christopher R.,Beck, Christopher A.,Cronin, Jason S.,Staszak, Michael A.
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Read Online
- Palladium(ii)-catalyzed γ-selective hydroarylation of alkenyl carbonyl compounds with arylboronic acids
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A catalytic γ-selective syn-hydroarylation of alkenyl carbonyl compounds using arylboronic acids has been developed using a substrate directivity approach with a palladium(ii) catalyst. This method tolerates a wide range of functionalized (hetero)arylboronic acids and a variety of substitution patterns on the alkene. Preliminary mechanistic studies suggest that transmetalation is rate-limiting.
- Matsuura, Rei,Jankins, Tanner C.,Hill, David E.,Yang, Kin S.,Gallego, Gary M.,Yang, Shouliang,He, Mingying,Wang, Fen,Marsters, Rohan P.,McAlpine, Indrawan,Engle, Keary M.
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p. 8363 - 8368
(2018/11/24)
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- Total Synthesis of Tedarene A
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Tedarene A is a macrocyclic diaryl ether heptanoid isolated from the marine sponge Tedania ignis showing an inhibitory effect against nitric oxide production. The first total synthesis of tedarene A was achieved starting from the commercially available 3-
- Maurent, Kelly,Vanucci-Bacqué, Corinne,Saffon-Merceron, Nathalie,Baltas, Michel,Bedos-Belval, Florence
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p. 1623 - 1630
(2017/05/31)
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- Discovery and Structure-Activity Relationships of the Neoseptins: A New Class of Toll-like Receptor-4 (TLR4) Agonists
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Herein, we report studies leading to the discovery of the neoseptins and a comprehensive examination of the structure-activity relationships (SARs) of this new class of small-molecule mouse Toll-like receptor 4 (mTLR4) agonists. The compounds in this class, which emerged from screening an α-helix mimetic library, stimulate the immune response, act by a well-defined mechanism (mouse TLR4 agonist), are easy to produce and structurally manipulate, exhibit exquisite SARs, are nontoxic, and elicit improved and qualitatively different responses compared to lipopolysaccharide, even though they share the same receptor.
- Morin, Matthew D.,Wang, Ying,Jones, Brian T.,Su, Lijing,Surakattula, Murali M. R. P.,Berger, Michael,Huang, Hua,Beutler, Elliot K.,Zhang, Hong,Beutler, Bruce,Boger, Dale L.
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supporting information
p. 4812 - 4830
(2016/06/13)
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- Compositions for Treatment of Cystic Fibrosis and Other Chronic Diseases
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The present invention relates to pharmaceutical compositions comprising an inhibitor of epithelial sodium channel activity in combination with at least one ABC Transporter modulator compound of Formula A, Formula B, Formula C, or Formula D. The invention also relates to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis using the pharmaceutical combination compositions.
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Paragraph 2211
(2015/09/22)
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- NEOSEPTINS: SMALL MOLECULE ADJUVANTS
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A MD-2:TLR4 complex agonist compound is disclosed whose structure corresponds to Formula (I), as defined within. Also disclosed are a method of its preparation and use, as well as a pharmaceutical composition containing the same.
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Page/Page column 131-132
(2014/09/03)
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- Histone deacetylase inhibitors
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This invention relates to novel Histone deacetylases inhibitors. Also disclosed is a method for treating mucositis or cancer with these inhibitors.
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Page/Page column 12
(2011/12/03)
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- HISTONE DEACETYLASE INHIBITORS
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This invention relates to novel Histone deacetylases inhibitors. Also disclosed is a method for treating mucositis or cancer with these inhibitors.
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Page/Page column 10
(2011/12/12)
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- COMPOSITIONS FOR TREATMENT OF CYSTIC FIBROSIS AND OTHER CHRONIC DISEASES
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The present invention relates to pharmaceutical compositions comprising an inhibitor of epithelial sodium channel activity in combination with at least one ABC Transporter modulator compound of Formula A, Formula B, Formula C, or Formula D. The invention also relates to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis using the pharmaceutical combination compositions.
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- G-PROTEIN-CONJUGATED RECEPTOR AGONIST
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Disclosed is a novel aralkyl carboxylic acid compound which has an agonistic activity on GPR-120 and/or GPR-40, particularly GPR-120, and is therefore useful as an appetite regulator, an anti-obesity agent, a therapeutic agent for diabetes, a pancreatic beta differentiating cell growth enhancer, a therapeutic agent for metabolic syndrome, a therapeutic agent for a gastrointestinal disease, a therapeutic agent for a neuropathy, a therapeutic agent for a mental disorder, a therapeutic agent for a pulmonary disease, a therapeutic agent for a pituitary hormone secretion disorder or a lipid flavoring/seasoning agent. The aralkyl carboxylic acid compound is represented by the general formula (I). (I) wherein the ring Q represents a pyridyl or the like; R1 represents a C1-6 alkyl group or the like; R2 represents a hydrogen atom, a C1-4 alkyl group or a C1-4 alkoxy group; m and n independently represent an integer of 1 to 5; and X represents an oxygen atom, a sulfur atom or - NR3- [wherein R3 represents a hydrogen atom or a C1-4 alkyl group].
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Page/Page column 29-30
(2010/03/02)
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- Organic Compounds
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A compound of Formula I in free or salt or solvate form, where R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and R11 have the meanings as indicated in the specification, is useful for treating diseases which respond to the blockade of the epithelial sodium channel. Pharmaceutical compositions that contain the compounds and processes for preparing the compounds are also described.
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Page/Page column 89
(2010/06/14)
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- ALKANOIC ACID DERIVATIVES AND THEIR THERAPEUTIC USE AS HDAC INHIBITORS
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The invention related to alkanoic acid derivatives of Formula (IIa) and (IIb). These compounds of the invention were found to have activity as HDAC inhibitors.
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Page/Page column 75
(2010/08/05)
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- Antileukotrienic phenethylamido derivatives of arylalkanoic acids in the treatment of ulcerative colitis
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A series of arylalkanoic acid derivatives bearing methyl(phenethyl)amino groups were prepared and their inhibition of LTB4 biosynthesis was evaluated. Regression analysis showed the slightly different parabolic dependences of this activity on lipophilicity of α-methyl and α-unsubstituted alkanoic acid derivatives. The relationship derived for α-unsubstituted alkanoic acids was extended by previously prepared group of similar derivatives of arylacetic acids without any change of regression coefficients and statistical criteria. It was concluded that the most active compounds belong to 2-arylpropanoic acid derivatives with lipophilicity close to log Popt (=6.97). But generally, the structural changes in the acidic part of compounds under study did not yield the substantial improvement of LTB4 biosynthesis inhibition in comparison with the previously prepared series of derivatives IV. The anti-inflammatory effect of the compounds under study was evaluated in three animal models of inflammation and their possible utilization in the treatment of ulcerative colitis (UC) was followed. From 12 evaluated compounds, 4 compounds are more active in UC inhibition than the standard sulfasalazine but it can be stated that the change of connecting chain between aromatic ring and carboxyl did not bring about the important improvement of this activity in comparison with previous derivatives of arylacetic acids. Possible relation between LTB4 biosynthesis inhibition and ulcerative colitis is seriously broken by the compound 8a with carbonyl as the additional functional group on the connecting chain between carboxyl and aromatic ring.
- Junek, Richard,Kverka, Miloslav,Jandera, Antonin,Panajotova, Vladimira,Satinsky, Dalibor,Machacek, Milos,Kuchar, Miroslav
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experimental part
p. 332 - 344
(2009/04/06)
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- CARBOXYLIC DERIVATIVES FOR USE IN THE TREATMENT OF CANCER
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The invention provides novel compounds of formula (I), wherein: R1 is a radical derived from one of the known ring systems; R2 is a phenyl radical optionally substituted; Xn represents a birradical selected from the group consisting of: -(CH2)1-4-, (C2-C4)-alkenyl, (C2-C4)alkynyl, -S-(CH2)1-3-#, and -(CH2)1-3-O-#; wherein the symbol # indicates the position at which Xn is attached to R1; Yn is a birradical selected from the group consisting of: -(CH2)2-4-, -S-(CH2)1-3#, and -O-(CH2)1-3-#,; where in the symbol # indicates the position at which Yn is attached to R2; and R3 is a radical selected from the group consisting of: -OR4. The compounds of formula (I) are useful in the treatment of cancer
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Page/Page column 20
(2009/07/25)
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- A facile synthesis of di-O-methyl centrolobol
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A facile route to (±)di-O-methyl centrolobol 4 has been explored starting from 4-oxo-4-(4-methoxyphenyl) butanoic acid 7 and 4-methoxycinnamic acid 13.
- Panda, Atulya Kumar
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p. 372 - 375
(2007/10/03)
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- Alkynyl containing hydroxamic acid compounds as matrix metalloproteinase and tace inhibitors
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Compounds of the formula are useful in treating disease conditions mediated by TNF-α, such as rheumatoid arthritis, osteoarthritis, sepsis, AIDS, ulcerative colitis, multiple sclerosis, Crohn's disease and degenerative cartilage loss.
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Page column 39
(2008/06/13)
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- Initial structure-activity relationship of a novel class of nonpeptidyl GnRH receptor antagonists: 2-arylindoles
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A nonpeptidyl GnRH receptor antagonist (1), with a unique 2-arylindole core, was identified through the Merck in-house screening for binding affinity on the rat GnRH receptor. SAR studies directed toward the alkoxy-ethanolamine and 2-aryl groups resulted in a simpler lead structure with improved activity. This compound 50 exhibits a 60-fold improvement in binding activity over our initial lead 1.
- Chu, Lin,Hutchins, Jennifer E.,Weber, Ann E.,Lo, Jane-Ling,Yang, Yi-Tien,Cheng, Kang,Smith, Roy G.,Fisher, Michael H.,Wyvratt, Matthew J.,Goulet, Mark T.
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p. 509 - 513
(2007/10/03)
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- Development and Evaluation of Antisera for Detection of the O,O-Diethyl Phosphorothionate and Phosphorothionothiolate Organophosphorus Pesticides by Immunoassay
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An immunochemical approach for class detection of organophosphorus pesticides was investigated. Synthesis of O,O-diethyl phosphorothionate haptens and their use in the generation of polyclonal antisera are described. An indirect inhibition format ELISA co
- Johnson, Jeffre C.,Van Emon, Jeanette M.,Pullman, Diane R.,Keeper, Kenneth R.
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p. 3116 - 3123
(2007/10/03)
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- Use of a dipeptide chemical library in the development of non-peptide tachykinin NK3 receptor selective antagonists
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The use of a dipeptide library as the source of a micromolar chemical lead compound for the human tachykinin NK3 receptor is described. The screening of a dipeptide library through a cloned human NK3 receptor binding assay resulted in the identification of Boc(S)Phe(S)PheNH2 (1), which has subsequently been developed, following a 'peptoid' design strategy, into a series of high-affinity NK3 receptor selective antagonists. The structure- activity relationship of the C-terminal portion of this dipeptide lead was first explored and led to the identification of the urea derivative Boc(S)Phe(R)αMePheNH(CH2)7NHCONH2 (41, PD157672). This modified dipeptide has a K(o) of 7 nM in blocking senktide-induced increases in intracellular calcium levels in human NK3 receptors stably expressed in CHO cells. Subsequent optimization of the N-terminal BocPhe group and the αMePhe residue side chain of 41 led to the identification of [S-(R*,S*)]-[2-(2,3- difluorophenyl)-1-methyl-1-[(7-ureidoheptyl)carbamoyl]ethyl]carbamic acid 2- methyl-1-phenylpropyl ester (60, PD161182), a non-peptide NK3 receptor selective antagonist. Compound 60 blocks the senktide-evoked increases in intracellular calcium levels in cloned human NK3 receptors stably expressed in CHO cells with K(e) of 0.9 nM.
- Boden, Phil,Eden, Jon M.,Hodgson, Julie,Horwell, David C.,Hughes, John,McKnight, Alexander T.,Lewthwaite, Russell A.,Pritchard, Martyn C.,Raphy, Jenny,Meecham, Ken,Ratcliffe, Giles S.,Suman-Chauhan, Nirmala,Woodruff, Geoffrey N.
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p. 1664 - 1675
(2007/10/03)
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- Synthesis and protein kinase C inhibitory activities of acyclic balanol analogs that are highly selective for protein kinase C over protein kinase A
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A series of balanol analogs in which the perhydroazepine ring and the p- hydroxybenzamide moiety were combined into an acyclic linked unit have been prepared and evaluated for their inhibitory properties against the serine/threonine kinase PKC. Several low-micromolar to lownanomolar inhibitors of the α, β'(I), β(II), γ, δ, ε, and η PKC isozymes were prepared. In general, these acyclic balanol analogs were found to be highly selective for PKC over the serine/threonine kinase PKA. The type and number of atoms linking the benzophenone ester to the p-hydroxyphenyl group necessary for optimal PKC inhibition were investigated. The most potent compounds contained a three-carbon linker in which the carboxamide moiety of balanol had been replaced by a methylene group. The effect of placing substituents on the three-carbon chain was also investigated. The preferred compounds contained either a 2-benzene-sulfonamido (6b) or a 1-methyl (21b) substituent. The preferred compounds 6b and 21b were tested against a panel of serine/threonine kinases and found to be highly selective for PKC. The more active enantiomer of 6b, (S)-12b, was 3-10-fold more active than the R- enantiomer against the PKC isozymes. The effect of making the analogs more rigid by making the three-carbon chain part of a five-membered ring, but with retention of the methylene replacement for the carboxamide moiety, led to potent PKC inhibitors including anti-substituted pyrrolidine analog 35b and the most potent PKC inhibitor in the series, anti-substituted cyclopentane analog 29b. The anti cyclopentane analog 29b was a low-micromolar inhibitor of the PMA-induced superoxide burst in neutrophils, and its carboxylic ester was a high-nanomolar inhibitor of neutrophils. Finally esterification of 21b, (S)-12b, and 35b turned these potent PKC inhibitors into low-micromolar inhibitors of neutrophils.
- Defauw, Jean M.,Murphy, Marcia M.,Jagdmann Jr., G. Erik,Hu, Hong,Lampe, John W.,Hollinshead, Sean P.,Mitchell, Thomas J.,Crane, Heidi M.,Heerding, Julia M.,Mendoza, José S.,Davis, Jefferson E.,Darges, James W.,Hubbard, Frederick R.,Hall, Steven E.
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p. 5215 - 5227
(2007/10/03)
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- Tri- and tetrapeptide analogues of kinins as potential renal vasodilators
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Tri- and tetrapeptide analogues were synthesized and evaluated as renal vasodilators. These peptides were prepared by standard coupling reactions which also provided good yields with hindered α-methyl amino acid derivatives. Preliminary evidence of renal vasodilator activity was determined in anesthetized dogs by measuring the effects on renal blood flow and calculating the accompanying changes in renal vascular resistance. The most potent compounds contained, in their structure, the L-prolyl-DL-α-methylphenylalanyl-L-arginine and L-prolyl-DL-α-methyl-phenyalanylglycyl-L-proline arrays. Substitution on the N-terminal proline with 4-phenylbutyryl and 4-(4-hydroxyphenyl)butyryl side chains produced enhanced renal vasodilator activity and, in certain cases, selectivity for the renal vasculature.
- Pfeiffer,Chambers,Hilbert,Woodward,Ackerman
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p. 325 - 341
(2007/10/02)
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- A Convenient Solvent-specific Synthesis of 4-butyric acid
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Three types of reaction, esterification, C-alkenylation, and O-alkenylation, have been observed between the di-anion (4) and 1-bromo-3-methylbut-2-ene (5) in different solvent systems.Our studies of the effect of the medium on the behavior of the di-anion (4) towards electrophilic attack by the bromo-alkene (5) resulted in the synthesis of analogues (2) and (6d) of a known anti-sickling agent (3) in high yiel.The regioselectivity of the alkylation reactions is rationalised in terms of solvent polarity.
- Fatope, Majekodunmi O.,Okogun, Joseph I.
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p. 1601 - 1604
(2007/10/02)
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