University of California

Università Degli Studi Di Parma

Università Degli Studi Di Urbino "carlo Bo"

Universita Degli Studi Di Urbino

Fondazione Istituto Italiano Di Technologia

Sigma-tau Industrie Farmaceutiche Riunite S.p.a.

Mcgill University

Fondazione Istituto Italiano Di Tecnologia

Universita′ Degli Studi Di Milano

Universita Degl Studi Di Parma

Giorgio Tarzia

Marco Mor

Daniele Piomelli

Andrea Duranti

Andrea Tontini

Tiziano Bandiera

Fabio Bertozzi

Patrizia Minetti

Angelo Mario Reggiani

Andrea Nuzzi

Annalisa Fiasella

Gilberto Spadoni

Stefano Ponzano

Guillermo Moreno-Sanz

Walter Cabri

Franco Fraschini

Maria Assunta Di Cesare

Chiara Pagliuca

Giovanni Piersanti

Gabriella Gobbi

Silvia Rivara

Annalida Bedini

Valeria Lucini

Jason R Clapper

Compounds and pharmaceutical compositions are contemplated that inhibit N-acyl-ethanolamine-hydrolyzing acid amidase (NAAA) to so increase the concentration of the substrate of NAAA, palmitoylethanolamide (PEA). NAAA inhibition is contemplated to be effective to alleviate conditions associated with a reduced concentration of PEA. Among other uses, various NAAA inhibitors are especially contemplated as therapeutic agents in the treatment of inflammatory diseases.

Compositions and methods of inhibiting N-acylethanolamine-hydrolyzing acid amidase

Described herein are compounds and pharmaceutical compositions which inhibit N-acylethanolamine acid amidase (NAAA). Described herein are methods for synthesizing the compounds set forth herein and methods for formulating these compounds as pharmaceutical compositions which include these compounds. Also described herein are methods of inhibiting NAAA in order to sustain the levels of palmitoylethanolamide (PEA) and other N-acylethanolamines (NAE) that are substrates for NAAA, in conditions characterized by reduced concentrations of NAE. Also, described here are methods of treating and ameliorating pain, inflammation, inflammatory diseases, and other disorders in which modulation of fatty acid ethanolamides is clinically or therapeutically relevant or in which decreased levels of NAE are associated with the disorder.

Amide derivatives of lactam based N-acylethanolamine acid amidase (NAAA) inhibitors

Carbamate derivatives of lactam based N-acylethanolamine acid amidase (NAAA) inhibitors

The present invention provides methods of making and using peripherally restricted inhibitors of fatty acid amide hydrolase (FAAH). The present invention provides compounds and compositions that suppress FAAH activity and increases anandamide levels outside the central nervous system (CNS). The present invention also sets forth methods for inhibiting FAAH as well as methods for treating conditions such as, but not limited to, pain, inflammation, immune disorders, dermatitis, mucositis, the over reactivity of peripheral sensory neurons, neurodermatitis, and an overactive bladder. Accordingly, the invention also provides compounds, methods, and pharmaceutical compositions for treating conditions in which the selective inhibition of peripheral FAAH (as opposed to CNS FAAH) would be of benefit.

Meta-substituted biphenyl peripherally restricted FAAH inhibitors

The present invention provides compounds and pharmaceutical compositions for inhibiting N-acylethanolamine acid amidase (NAAA). Inhibition of NAAA is contemplated as a method to sustain the levels of palmitoylethanolamide (PEA) and oleylethanolamide (OEA), two substrates of NAAA, in conditions characterized by reduced concentrations of PEA and OEA. The invention also provides methods for treating inflammatory diseases and pain, and other disorders in which decreased levels of PEA and OEA are associated with the disorder.

Disubstituted beta-lactones as inhibitors of N-acylethanolamine acid amidase (NAAA)

Peripherally restricted inhibitors of fatty acid amide hydrolase (FAAH) are provided. The compounds can suppress FAAH activity and increases anandamide levels outside the central nervous system (CNS). Despite their relative inability to access brain and spinal cord, the compounds attenuate behavioral responses indicative of persistent pain in rodent models of inflammation and peripheral nerve injury, and suppresses noxious stimulus-evoked neuronal activation in spinal cord regions implicated in nociceptive processing. CBi receptor blockade prevents these effects. Accordingly, the invention also provides methods, and pharmaceutical compositions for treating conditions in which the inhibition of peripheral FAAH would be of benefit. The compounds of the invention are according to the formula (I): in which Ris a polar group. In some embodiments, Ris selected from the group consisting of hydroxy and the physiologically hydro lysable esters thereof. Rand Rare independently selected from the group consisting of hydrogen and substituted or unsubstituted hydrocarbyl; each Ris independently selected from the group consisting of halogen and substituted or unsubstituted hydrocarbyl and n is an integer from 0 to 4; each Ris independently selected from the group consisting of halo and substituted or unsubstituted hydrocarbyl and m is an integer from 0 to 3; and Ris substituted or unsubstituted cyclohexyl; and the pharmaceutically acceptable salts thereof. 

Peripherally restricted FAAH inhibitors

The present invention relates to new triazolyl purine derivatives of formula (I), processes for their preparation, and to pharmaceutical compositions containing them for the treatment of neurological disorders or cerebral ischaemia for which inhibition of adenosine A2A receptor will result at improving the health state of a patient.

Oxidated derivatives of triazolylpurines useful as ligands of the adenosine A2A receptor and their use as medicaments

Novel melatonin ligands of Formula I: or pharmaceutically acceptable salts thereof wherein: n is 1 or 2; m is 0, 1 or 2; p is 0, 1, 2, 3, 4, 5, 6, 7 or 8; v is 2 or 3; A is aryl or heteroaryl; Z is O, S or NR; Y is selected from the group consisting of hydrogen, aryl, heteroaryl, C-Calkyl, C-Ccycloalkyl, and R is selected from the group consisting of hydrogen, hydroxyl, &#x2014;OCF, CF, C-Calkyl, C-Calkyloxy, C-Calkylthio, halogen and &#x2014;Z&#x2014;(CH)-A; Ris selected from the group consisting of C-Calkyl, C-Ccycloalkyl, CF, hydroxy-substituted C-Calkyl, hydroxy-substituted C-Ccycloalkyl, and NHR, wherein Ris C-Calkyl or C-Ccycloalkyl; Ris selected from the group consisting of: hydrogen, C-Calkyl, C-Calkyloxy, OCF, CF, hydroxyl, and halogen; Ris selected from the group consisting of hydrogen, C-Calkyl, C-Calkyloxy, OCF, CF, hydroxyl, and halogen; R and Rmay be connected together to form an &#x2014;O&#x2014;(CH)bridge representing with the carbon atoms to which they are attached a 5- or 6-membered heterocyclic ring system; Ris selected from the group consisting of hydrogen, C-Calkyl, C-Calkyloxy, OCF, CF, hydroxyl, and halogen; Ris selected from the group consisting of hydrogen and C-Calkyl; Ris selected from the group consisting of hydrogen, C-Calkyl, C-Calkyloxy, OCF, CF, hydroxyl, and halogen; and Ris selected from the group consisting of hydrogen and C-Calkyl.

Melatonin ligands having antidepressant activity as well as sleep inducing properties

Fatty acid amide hydrolase inhibitors of the Formula: are provided wherein X is NH, CH, O, or S; Q is O or S; Z is O or N; R is an aromatic moiety selected from the group consisting of substituted or unsubstituted aryl; substituted or unsubstituted biphenylyl, substituted or unsubstituted naphthyl, and substituted or unsubstituted phenyl; substituted or unsubstituted terphenylyl; substituted or unsubstituted cycloalkyl, heteroaryl, or alkyl; and Rand Rare independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, and substituted or unsubstituted phenyl, substituted or unsubstituted biphenylyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; with the proviso that if Z is O, one of Rand Ris absent, and that if Z is N, optionally Rand Rmay optionally be taken together to form a substituted or unsubstituted N-heterocycle or substituted or unsubstituted heteroaryl with the N atom to which they are each attached. Pharmaceutical compositions comprising the compounds of Formula I and methods of using them to inhibit FAAH and/or treat appetite disorders, glaucoma, pain, insomnia, and neurological and psychological disorders including anxiety disorders, epilepsy, and depression are provided.

Modulation of anxiety through blockade of anandamide hydrolysis

Compounds of Formula (I): (I); wherein: Rand Reither the same or different, are H or linear or branched C&#x2013;Calkyl; R=linear or branched C&#x2013;Calkyl; R=halogen, and pharmaceutically acceptable salts thereof are useful as active ingredients in the preparation of medicaments used as ligands of the 5-HTand/or 5-HTserotoninergic receptors.

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Petriano, Italy

Giorgio Tarzia