87661-18-5Relevant articles and documents
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.
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.
