- A Novel Agonist of the Type 1 Lysophosphatidic Acid Receptor (LPA1), UCM-05194, Shows Efficacy in Neuropathic Pain Amelioration
-
Neuropathic pain (NP) is a complex chronic pain state with a prevalence of almost 10% in the general population. Pharmacological options for NP are limited and weakly effective, so there is a need to develop more efficacious NP attenuating drugs. Activation of the type 1 lysophosphatidic acid (LPA1) receptor is a crucial factor in the initiation of NP. Hence, it is conceivable that a functional antagonism strategy could lead to NP mitigation. Here we describe a new series of LPA1 agonists among which derivative (S)-17 (UCM-05194) stands out as the most potent and selective LPA1 receptor agonist described so far (Emax = 118%, EC50 = 0.24 μM, KD = 19.6 nM; inactive at autotaxin and LPA2-6 receptors). This compound induces characteristic LPA1-mediated cellular effects and prompts the internalization of the receptor leading to its functional inactivation in primary sensory neurons and to an efficacious attenuation of the pain perception in an in vivo model of NP.
- González-Gil, Inés,Zian, Debora,Vázquez-Villa, Henar,Hernández-Torres, Gloria,Martínez, R. Fernando,Khiar-Fernández, Nora,Rivera, Richard,Kihara, Yasuyuki,Devesa, Isabel,Mathivanan, Sakthikumar,Del Valle, Cristina Rosell,Zambrana-Infantes, Emma,Puigdomenech, María,Cincilla, Giovanni,Sanchez-Martinez, Melchor,Rodríguez De Fonseca, Fernando,Ferrer-Montiel, Antonio V.,Chun, Jerold,López-Vales, Rubén,López-Rodríguez, María L.,Ortega-Gutiérrez, Silvia
-
p. 2372 - 2390
(2020/01/02)
-
- INSULIN CONJUGATES
-
The present invention relates to a conjugate comprising a sulfonamide of formula (I) and an active pharmaceutical ingredient such as an insulin analog comprising at least one mutation relative to the parent insulin, wherein the insulin analog comprises a mutation at position B16 which is substituted with a hydrophobic amino acid and/or a mutation at position B25 which is substituted with a hydrophobic amino acid. The present invention further relates to a sulfonamide of formula (A). Moreover, the present invention relates to an insulin analog comprising at least one mutation relative to the parent insulin.
- -
-
Paragraph 0580-0583
(2020/07/05)
-
- Amantadine hapten and preparing method and application thereof
-
The invention relates to the field of preparation of haptens, in particular to an amantadine hapten and a preparing method and application thereof. When the amantadine hapten is prepared, amantadine and bromine polyhydroxyalkanoate serve as raw materials, and through a nucleophilic substitution reaction, amidogen groups in amantadine molecules are connected with the bromine polyhydroxyalkanoate; then through a hydrolysis reaction, carboxyl groups are introduced to obtain a corresponding product. The amantadine hapten can be coupled with a carrier protein to prepare an artificial antigen, the artificial antigen is prepared into a monoclonal antibody or a polyclonal antibody through an immune animal, and then the monoclonal antibody or the polyclonal antibody can be used for quickly detecting residues of the amantadine in an animal product.
- -
-
Paragraph 0074; 0076; 0082
(2019/10/01)
-
- Synthesis of antifungal alatanone and trineurone polyketides
-
The antifungal polyketides alatanones A and B and trineurones A–E have been synthesized using a one-pot C-acylation reaction coupling 1,3-cyclohexanediones with the appropriate carboxylic acids. This key transformation is believed to proceed via initial carbodiimide-mediated O-acylation followed by a DMAP-catalyzed Claisen–Haase rearrangement, resulting in O to C acyl migration.
- Lewis, Alexander R.,Reber, Keith P.
-
supporting information
p. 1083 - 1086
(2018/03/23)
-
- Synthesis of fluorescent C24-ceramide: Evidence for acyl chain length dependent differences in penetration of exogenous NBD-ceramides into human skin
-
Topical skin lipid supplementation may provide opportunities for controlling ceramide (Cer) deficiency in skin diseases such as atopic dermatitis or psoriasis. Here we describe the synthesis of a long-chain 7-nitrobenzo[c][1,2,5]oxadiazol-4-yl (NBD)-labeled Cer and its different penetration through human skin compared to widely used short-chain fluorescent Cer tools.
- Novotny, Jakub,Pospěchová, Kate?ina,Hrabálek, Alexandr,?áp, Robert,Vávrová, Kate?ina
-
supporting information; experimental part
p. 6975 - 6977
(2010/06/16)
-
- Benzimidazole compounds containing 1,2,4-triazole ring, and compositions and methods of use containing the same
-
Benzimidazole compounds represented by the formula set out below and analogs thereof, wherein Y represents a single bond or sulfur atom; Z represents oxygen atom, sulfur atom, or N--R4 ; R1 and R2 independently represent hydrogen, a halogen atom, alkyl group or other; R1 and R4 independently represent hydrogen, alkyl group, acyl group or other; n and m independently represent an integer of 1, 2, or 3; and L represents a linking group such as C2-12 alkylene group or an alkylene group containing one or more phenylene groups or ether groups. The compounds are useful as an active ingredient of a medicament such as a preventive and therapeutic medicament for hyperlipemia or arterial sclerosis. STR1
- -
-
-
- Multiple Electron Tunneling Paths across Self-Assembled Monolayers of Alkanethiols with Attached Ruthenium(II/III) Redox Centers
-
Alkanethiol monolayers with pendant redox centers are deposited on gold electrodes by selfassembly.The monolayers are composed of both an electroactive thiol, HS(CH2)nC(O)NHCH2pyRu(NH3)5(2+/3+), with 10-15 methylene groups, and a diluent thiol, HS(CH2)mCOOH, also with 10-15 methylene groups.The monolayers are classified as "matched" (n = m), "exposed" ( n = 15, m = 10-14), and "buried" (n = 10, m = 11-15) according to the relative position of the redox center.Cyclic voltammograms in aqueous Na2SO4 indicate that the monolayers are close-packed with the redox centers residing in the aqueous phase in all but the most buried cases.Measurements of electron transfer kinetics by several methods (cyclic voltammetry, ac impedance spectroscopy, chronoamperometry) yield an internally consistent set of kinetic parameters, the standard rate constant ko, and the reorganization energy λ of the redox centers.The reorganization energies are in good agreement with the theoretically predicted value of 1.0 eV for the pyRu(NH3)5 redox centers.Plots of ln(ko) vs m are linear in all three cases.The slopes of the linear regression fit provide tunneling parameters (β, where ko ca. e-βm) of 0.97 +/- 0.03 (matched cases), 0,83 +/- 0.03 (exposed cases) and 0.16 +/- 0.02 (buried cases) per methylene.This pattern of β's is interpreted in terms of electronic coupling between the redox center and the electrode via both the redox thiol and the proximate diluent thiols, with the coupling via the diluent thiols dominating in the exposed cases.
- Finklea, Harry O.,Liu, Luna,Ravenscroft Melissa S.,Punturi, Sesto
-
p. 18852 - 18858
(2007/10/03)
-
- Synthesis of ω-Unsaturated Acids
-
A short, high-yield method for the synthesis of ω-unsaturated acids have been developed that precludes any double-bond migration or hydrogenation.Key is the coupling reaction between Grignards of ω-unsaturated alkyl halides and the bromomagnesium salt of ω-bromo fatty acids.The reaction has been successfully extended to ω-bromo nitriles.The use of ω-chloro acids or α-bromo acids gives lower yields of heterocoupling products and substantial homocoupling.A catalyst study shows Li2CuCl4 to yield the most heterocoupling of several catalysts tried for the chloro acids, and Ni(II) or Cu(I) are best for the α-bromo acids.
- Mirviss, Stanley B.
-
p. 1948 - 1951
(2007/10/02)
-
- Synthesis of even C24-C30 primary normal aliphatic alcohols from cyclododecanone
-
A simple method has been developed for the oxidation of cyclododecanone by sodium persulfate in an aqueous methanol solution of sulfuric acid to give 12-hydroxydodecanoic acid, which upon treatment with HBr in acetic acid gives 12-bromododecanoic acid with RMgX, where R=C12H25, C14H29, C16H33, and C18H37 in THF in the presence of Li2CuCl4 and subsequent reduction of the salts of the alkanecarboxylic acids by LiAlH4 give primary even normal C24-C30 alcohols.
- Zakharkin, L. I.,Churilova, I. M.,Anikina, E. V.
-
-
- Convenient Syntheses of Bifunctional C12-Acyclic Compounds from Cyclododecanone
-
The conversion of cyclododecanone by convenient, non-hazardous, and high-yielding reactions into a set of useful C12-bifunctional intermediates is described.Baeyer-Villiger oxidation and hydrolysis give a hydroxy acid, successively converted into the bromo acid, bromo alcohol, crude bromo aldehyde, pure bromo aldehyde ethylene acetal, and pure bromo aldehyde.Preferred reagents for the transformation CO2H -> CHO are borane-dimethyl sulphide followed by dimethyl sulphoxide-oxalyl dichloride-triethylamine.
- Bidd, Ilesh,Kelly, David J.,Ottley, Peter M.,Paynter, Oliver I.,Simmonds, Derek J.,Whiting, Mark C.
-
p. 1369 - 1372
(2007/10/02)
-
- The Synthesis of Long-chain Unbranched Aliphatic Compounds by Molecular Doubling
-
A convenient general synthesis, applicable to alkanes and terminally mono- and di-substituted alkanes of any chain length, is described; cyclododecanone is used as the starting material, and the C12 chain is doubled in length as often as required and adjusted first to a multiple of 12, and then to any desired length.
- Paynter, Oliver I.,Simmonds, Derek J.,Whiting, Mark C.
-
p. 1165 - 1166
(2007/10/02)
-