87661-18-5Relevant academic research and scientific papers
New orally active dual enkephalinase inhibitors (DENKIs) for central and peripheral pain treatment
Poras, Hervé,Bonnard, Elisabeth,Dangé, Emilie,Fournié-Zaluski, Marie-Claude,Roques, Bernard P.
supporting information, p. 5748 - 5763 (2014/08/05)
Protecting enkephalins, endogenous opioid peptides released in response to nociceptive stimuli, is an innovative approach for acute and neuropathic pain alleviation. This is achieved by inhibition of their enzymatic degradation by two membrane-bound Zn-metallopeptidases, neprilysin (NEP, EC 3.4.24.11) and aminopeptidase N (APN, EC 3.4.11.2). Selective and efficient inhibitors of both enzymes, designated enkephalinases, have been designed that markedly increase extracellular concentrations and half-lives of enkephalins, inducing potent antinociceptive effects. Several chemical families of Dual ENKephalinase Inhibitors (DENKIs) have previously been developed but devoid of oral activity. We report here the design and synthesis of new pro-drugs, derived from co-drugs combining a NEP and an APN inhibitor through a disulfide bond with side chains improving oral bioavailability. Their pharmacological properties were assessed in various animal models of pain targeting central and/or peripheral opioid systems. Considering its efficacy in acute and neuropathic pain, one of these new DENKIs, 19-IIIa, was selected for clinical development.
AMINOPHOSPHINIC DERIVATIVES THAT CAN BE USED IN THE TREATMENT OF PAIN
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Page/Page column 18, (2011/06/19)
The present invention relates to a compound of the following general formula (I): R1—NH—CH(R2)—P(═O)(OR3)—CH2—C(R4)(R5)—CONH—CH(R6)—COOR7 (I) or a pharmaceutically acceptable salt of the latter, an isomer or a mixture of isomers in any proportions, especially a mixture of enantiomers, and in particular a racemic mixture, for which R1 represents a —C(═O)—O—C(R8)(R9)—OC(═O)—R10 group; R2 represents an optionally substituted hydrocarbon-based chain, an aryl or heteroaryl group or a methylene group substituted by a heterocycle; R3 represents a hydrogen atom or a —C(R12)(R13)—OC(═O)—R14 group; R4 and R5 form, together with the carbon that bears them, a saturated hydrocarbon-based ring or an optionally substituted piperidine ring or R4 represents a hydrogen atom and R5 represents a phenyl or a benzyl that is optionally substituted, a heteroaromatic ring or a methylene group substituted by a heterocycle; R6 represents an optionally substituted hydrocarbon-based chain or a phenyl or a benzyl that is optionally substituted; and R7 represents a hydrogen atom or a benzyl, alkyl, heteroaryl, alkylheteroaryl, —CHMe—COOR18, —CHR19—OC(═O)OR20 and —CHR19—OC(═O)OR20 group. The present invention also relates to the use of these compounds as a medicinal product, and in particular for the treatment of pain, more advantageously neuropathic and neuroinflammatory pain, to their method of synthesis and also to the compositions containing them.
The relative reactivities of various unsaturated compounds towards diisopropyloxy(η2-cyclopentene)titanium
Cadoret, Frédéric,Six, Yvan
, p. 5491 - 5495 (2008/02/10)
Competition experiments were performed by adding pre-formed solutions of diisopropyloxy(η2-cyclopentene)titanium in diethyl ether to various mixtures of unsaturated compounds at low temperature, establishing the following reactivity scale: aldehyde > nitrile > ketone > terminal alkyne > internal alkyne > terminal alkene > ester, carbonate.
DERIVATIVES OF PHOSPHINIC ACID USEFUL AS ENDOTHELIN CONVERTING ENZYME INHIBITORS
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, (2008/06/13)
Phosphinic acid derivatives of the structural formula STR1 or a pharmaceutically acceptable salt thereof, wherein R is H, alkyl or alkanoyloxymethylene;R 1, R 2, R 3 and R. sub.4 are H, alkyl, alkenyl, alkenylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxyalkyl, carboxyalkyl, thioalkyl, alkoxythioalkyl, aminoalkyl, alkylaminoalkyl, cycloalkyl-substituted alkyl or heterocycloalkyl; or R 1 and R 2 form a cycloalkyl ring of 3-8 members and R 3 and R 4 are as defined; or R 3 and R 4 form a cycloalkyl ring of 3-7 members and R 1 and R 2 are as defined; or R 1 and R 2 together, and R 3 and R 4 together, each form a cycloalkyl ring;R 5 is--OR. sub.9 or--NHR 9, wherein R. sub.9 is hydrogen or alkyl;n is 0 or 1;A. sub.1 is p-aminobenzoyl or p-aminobenzenesulfonyl, or A 1 and R 5 together form a radical of an α-aminoacyl derivative; andR. sub.6 is phenylmethoxycarbonyl, arylcarbonyl, heteroarylcarbonyl or--A 2--R. sub.7, wherein A 2 is a divalent α-aminoacyl radical, and R 7 is a substituent on the α-amino atom selected from H, R 8 OCO--, R. sub.8 SO 2--and R 8 NHCO--, wherein R 8 is aryl, arylmethyl or (C. sub.1-C 8)alkyl;are disclosed for use as endothelin converting enzyme inhibitors; also disclosed are a genus of novel compounds wherein R 3 and R 4 form a cycloalkyl ring, and pharmaceutical compositions comprising said novel compounds.
Mercaptoacyl amino acid inhibitors of atriopeptidase. 1. Structure- activity relationship studies of methionine and S-alkylcysteine derivatives
Neustadt,Smith,Nechuta,Bronnenkant,Haslanger,Watkins,Foster,Sybertz
, p. 2461 - 2476 (2007/10/02)
A broad series of N-(3-mercaptoacyl) amino acid derivatives was evaluated for their ability to inhibit atriopeptidase (neutral endopeptidase, EC 3.4.24.11) in vitro and in vivo. Structural parameters studied were (i) the substituent on the 2-position of the 3-mercaptopropionyl moiety, (ii) the amino acid component, (iii) the S-terminal derivative, and (iv) the C- terminal derivative. Optimum activity was observed for derivatives of methionine and S-alkylcysteines. N-[3-Mercapto-2(S)-[(2- methylphenyl)methyl]-1-oxopropyl]-L-methionine was identified as a highly effective inhibitor of atriopeptidase meriting evaluation as a potential cardiovascular therapeutic agent.
Asymmetric Synthesis of (-)-(1R,2S)-Cispentacin and Related cis- and trans-2-Amino Cyclopentane- and Cyclohexane-1-carboxylic Acids
Davies, Stephen G.,Ichihara, Osamu,Lenoir, Isabelle,Walters, Iain A. S.
, p. 1411 - 1416 (2007/10/02)
The antifungal antibiotic (-)-(1R,2S)-2-aminocyclopentane-1-carboxylic acid (cispentacin) 8 and its cyclohexane homologue 14 have been prepared utilizing the highly stereoselective conjugate addition of homochiral lithium N-benzyl-N-α-methylbenzylamide 5.
