Method of screening non-peptide, non-steroid invertebrate pheromone compounds having mitogen-activated protein kinase modulating activity and compositions containing the same

Abstract

A method of screening pheromone compounds for mitogen-activated protein (MAP) kinase modulating activity and for employing such pheromone compounds in compositions suitable for the prevention or treatment of diseases, conditions, and symptoms thereof benefitting from modulation of MAP kinase activity.

1 . A method of screening compounds to obtain those having mitogen-activated protein (MAP) kinase modulating activity, comprising the steps of: 
 a) providing a biological model for screening of compounds having MAP kinase modulating activity, the model being predictive for MAP kinase modulating activity;    b) testing a group of invertebrate-derived non-peptide, non-steroid pheromone compounds in the biological model to determine the presence of MAP kinase modulating activity; and    c) selecting at least one of the pheromone compounds possessing MAP kinase modulating activity in the model to obtain at least one selected pheromone compound.    
     
     
         2 . The method of  claim 1  wherein the MAP kinase modulating activity is MAP kinase inhibiting activity.  
     
     
         3 . The method of  claim 1  wherein the MAP kinase modulating activity is MAP kinase activating activity.  
     
     
         4 . The method of  claim 1  further comprising the steps of: 
 adding said pheromone compounds to a culture containing cells capable of expressing MAP kinase activity to form a test sample;    adding a stimulator of MAP kinase to said test sample;    measuring the amount of MAP kinase activity; and    comparing the same to a control sample containing no pheromone compound.    
     
     
         5 . The method of  claim 1  further comprising the steps of: 
 treating a culture containing cells capable of expressing MAP kinase activity with a stimulator of MAP kinase;    adding said pheromone compounds to the culture;    measuring the amount of MAP kinase activity; and    comparing the same to a control sample containing no pheromone compound.    
     
     
         6 . A pharmaceutical composition comprising an effective amount of a selected compound obtained by the method of  claim 1  in combination with a pharmaceutically acceptable carrier.  
     
     
         7 . (canceled).  
     
     
         8 . A pharmaceutical composition comprising an effective amount of a pheromone compound having MAP kinase modulating activity in combination with a pharmaceutically acceptable carrier.  
     
     
         9 . The pharmaceutical composition of  claim 8  wherein the effective amount is from about 0.1 to 200 mg/kg/day.  
     
     
         10 . The pharmaceutical composition of  claim 9  wherein the effective amount is from about 2.0 to 180 mg/kg/day.  
     
     
         11 . The pharmaceutical composition of  claim 8  wherein the pheromone compound has a molecular weight of less than about 500 Daltons.  
     
     
         12 . The pharmaceutical composition of  claim 8  wherein the pheromone compound has a straight or branched saturated or unsaturated hydrocarbon chain having from about 6 to 30 carbon atoms.  
     
     
         13 . The pharmaceutical composition of  claim 12  wherein the pheromone compound has a straight or branched saturated or unsaturated hydrocarbon chain having from about 9 to 21 carbon atoms.  
     
     
         14 . The pharmaceutical composition of  claim 12  wherein the hydrocarbon chain is substituted with at least one member selected from the group consisting of an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a hydroxyl, a halide, an amine, a thiol, a thioester, a ketone, an aldehyde, an epoxy group, a carboxylic acid, an ester, an aromatic group, and a heterocyclic group.  
     
     
         15 . The pharmaceutical composition of  claim 8  wherein the pheromone compound is selected from the group consisting of cis-7-tetradecenal, cis-7-tetradecenol, cis-7-dodecenyl ester, heneicosene-11-one, cis-6-heneicosene-11-one, cis-4-tridecenyl ester, cis-4-tridecen-1-yl ester, 2-heptanone, cis-7-tetradecenyl ester, trans-5-decenyl ester, cis-2-methyl-7-octadecene, cis-9-heneicosene, trans-2, cis-13-octadecadienal, 14-methyl-cis-8-hexadecenal, 2-methyl-3-butene-2-ol, trans-10-dodecenol, cis-9-tetradecenyl-formate, cis-9-tetradecenol, trans-3, cis-8, cis-11-tetradecatrienol, cis-7-tridecenol, cis-9-pentadecenol, cis-9-undecenyl ester, trans-3, cis-7-tetradecadienyl ester and trans-3, cis-8-tetradecadienyl ester.  
     
     
         16 . The pharmaceutical composition of  claim 15  wherein the ester is an acetate.  
     
     
         17 . The pharmaceutical composition of  claim 8  wherein the pheromone compound inhibits MAP kinase activity.  
     
     
         18 . The pharmaceutical composition of  claim 17  wherein the MAP kinase inhibiting compound is selected from the group consisting of trans-3, cis-7-tetradecadienyl ester and trans-3, cis-8-tetradecadienyl ester.  
     
     
         19 . The pharmaceutical composition of  claim 8  wherein the pheromone compound activates MAP kinase activity.  
     
     
         20 . The pharmaceutical composition of  claim 19  wherein the MAP kinase activating compound is selected from the group consisting of cis-7-tetradecenal, cis-7-tetradecenol, cis-7-dodecenyl ester, heneicosene-11-one, cis-6-heneicosene-11-one, cis-4-tridecenyl ester, cis-4-tridecen-1-yl ester, 2-heptanone, cis-7-tetradecenyl ester, trans-5-decenyl ester, cis-2-methyl-7-octadecene, cis-9-heneicosene, trans-2, cis-13-octadecadienal, 14-methyl-cis-8-hexadecenal, 2-methyl-3-butene-2-ol, trans-10-dodecenol, cis-9-tetradecenyl-formate, cis-9-tetradecenol, trans-3, cis-8, cis-11-tetradecatrienol, cis-7-tridecenol, cis-9-pentadecenol, and cis-9-undecenyl ester.  
     
     
         21 . The pharmaceutical composition of  claim 20  wherein the ester is an acetate.  
     
     
         22 - 27 . (canceled).  
     
     
         29 . A method of selecting compounds having MAP kinase modulating activity, comprising the steps of: 
 a) providing data relating to the three-dimensional (3D) structure of at least one pharmacophore of a compound known to possess MAP kinase modulating activity;    b) providing a library of compounds, the library comprising at least one pheromone compound selected from invertebrate-derived, non-peptide, and non-steroid pheromones; and    c) analyzing the 3D structure of one or more compounds of the library and selecting a compound having a domain with a 3D structure at least substantially similar to the 3D structure of the pharmacophore.    
     
     
         30 . The method of  claim 29  wherein the MAP kinase activity is MAP kinase inhibiting activity.  
     
     
         31 . The method of  claim 29  wherein the MAP kinase activity is MAP kinase activating activity.  
     
     
         32 . The method of  claim 29  further comprising the steps of: 
 providing a biological model for screening of compounds having MAP kinase modulating activity, the model being predictive for MAP kinase modulating activity;    testing the selected compounds in the biological model for determining presence of MAP kinase modulating activity in tested pheromone compound thereof; and    selecting at least one of said compounds showing MAP kinase modulating activity to obtain at least one selected compound.    
     
     
         33 . A pharmaceutical composition comprising an effective amount of a selected compound obtained by the method of  claim 29  in combination with a pharmaceutically acceptable carrier.  
     
     
         34 . A method of modulating MAP kinase activity comprising administering to a warm-blooded animal an effective amount of the composition of  claim 33 .  
     
     
         35 . The method of claim  22  wherein the disease, condition, or symptom thereof is selected from the group consisting of cancer, autoimmune disease, psoriasis, restenosis, and cardiovascular disease.