Kallikrein 7 modulators

Abstract

The present invention relates to the crystal structure of the serine protease kallikrein 7 and to the use of this crystal structure in drug discovery. The present invention also relates to compounds binding specifically to this active site of kallikrein 7.

1 . A crystal of human kallikrein 7 comprising the binding pocket having a three-dimensional structure characterized by the structure coordinates of Table 3. 
     
     
         2 . The crystal of  claim 1  further comprising a co-crystallised ligand. 
     
     
         3 . A computer readable medium comprising data storage material encoded with computer readable data wherein said data comprises the structure coordinates of a crystal according to  claim 1 . 
     
     
         4 . Use of a crystal according to any one of  claim 1  or  2 , for the generation of crystal structure data. 
     
     
         5 . A method of identifying a ligand that binds to kallikrein 7 comprising the steps of:
 (i) generating a three dimensional structure data using the crystal structure data of  claim 1  to select and/or design a potential ligand that binds to kallikrein 7, and   (ii) identifying among the potential ligand selected in step (i), those ligands that bind to kallikrein 7 in an in vitro, in vivo or cell-based assay.   
     
     
         6 . A modulator of kallikrein 7 characterised in that it binds in the binding pocket having a three-dimensional structure characterized by the structure coordinates of Table 3. 
     
     
         7 . A modulator of kallikrein 7 as defined in  claim 6  characterised in that it is a compound of formula 
       
         
           
           
               
               
           
         
       
       Or a salt thereof wherein
 R 1  is hydrogen, cyano, (C 1-8 )alkyl, (C 2-8 )alkenyl, (C 2-8 )alkynyl, halogen, (C 1-8 )alkylamino, (C 1-8 )alkylamino(C 1-8 )alkyl, (C 1-8 )alkoxy, halo(C 1-8 )alkyl, 
 X is CH═CH, NH, N═CH, O or S, 
 Y is a group of formula 
 
       
         
           
           
               
               
           
         
       
       wherein
 the N-containing ring system is optionally annelated with (C 3-8 )cycloalkyl, (C 8-18 )aryl or heterocyclyl having 5 to 6 ring members and 1 to 4 heteroatoms selected from N, O, S, 
 n is 1, 2 or 3, 
 R 2  is
 (C 1-8 )alkyl, (C 1-8 )alkylamino, (C 1-8 )alkylamino(C 1-8 )alkyl, di(C 1-8 )alkylamino(C 1-8 )alkyl, halo(C 1-8 )alkyl, (C 1-8 )alkoxy, (C 1-8 )alkoxy(C 1-8 )alkyl, or 
 (CH 2 ) m -Z, wherein Z is unsubstituted or substituted (C 3-8 )cycloalkyl, (C 8-18 )aryl or heterocyclyl having 5 to 6 ring members and 1 to 4 heteroatoms selected from N, O, Si; and 
 
 m is 0, 1 or 2, 
 R 3  is hydrogen, (C 1-8 )alkyl, (C 1-8 )alkoxy, (C 8-18 )aryl or heterocyclyl having 5 to 6 ring members and 1 to 4 heteroatoms selected from N, O, S. 
 
     
     
         8 . A compound according to  claim 7 , wherein
 R 1  is hydrogen, ethynyl, chloro or bromo,   X is CH═CH or S,   Y is a group of formula (II), wherein
 the N-containing ring system is optionally annelated with cyclopropyl, cyclopentyl or phenyl, 
 n is 1 or 2, 
 R 2  is (C 1-8 )alkyl, (C 1-4 alkylamino, di(C 1-4 )alkylamino(C 1-4 )alkyl, (C 1-4 )alkoxy, (C 1-4 )alkoxy(C 1-4 )alkyl or 
 a group (CH 2 ) m -Z, wherein Z is unsubstituted cyclohexyl, unsubstituted phenyl, phenyl substituted by (C 1-4 )alkoxy, phenyl substituted by heterocyclyl having 6 ring members and 1 or 2 heteroatoms selected from N, O, or 
 unsubstituted or substituted heterocyclyl having 6 ring members and 1 or 2 heteroatoms selected from N, 0; 
   m is 1 or 2,   R 3  is hydrogen or (C 1-4 )alkoxy.   
     
     
         9 . A compound of  claim 7 , wherein
 Y is a group of formula (II), wherein
 the N-containing ring system is optionally annelated with cyclopropyl, cyclopentyl or phenyl, 
 R 2  is methyl, dimethylaminoethyl, methoxyethyl, or 
 a group (CH 2 ) m -Z, wherein Z is unsubstituted cyclohexyl, unsubstituted phenyl, phenyl substituted by methoxy, piperazinyl or morpholinyl; 
 pyridinyl, piperidinyl, tetrahydrofuranyl, unsubstituted piperazinyl or piperazinyl substituted by methyl or phenyl, 
   and m, n, R 1 , R 3  and X are as defined above.   
     
     
         10 . A compound of  claim 7  in the form of a salt. 
     
     
         11 . A compound of  claim 7  for use as a pharmaceutical. 
     
     
         12 . A pharmaceutical composition comprising a compound of  claim 7  in association with at least one pharmaceutical excipient. 
     
     
         13 . A method of treating disorders mediated by kallikrein-7 activity, which treatment comprises administering to a subject in need of such treatment an effective amount of a compound of  claim 7 . 
     
     
         14 - 15 . (canceled) 
     
     
         16 . The method of claim  14  wherein said disorder which is mediated by kallikrein-7 activity is selected from the group consisting of inflammatory and/or hyperpoliferative and pruritic skin diseases such as keloids, hypertrophic scars, acne, atopic dermatitis, psoriasis, pustular psoriasis, rosacea, Netherton's syndrome or other pruritic dermatoses such as prurigo nodularis, unspecified itch of the elderly as well as other diseases with epithelial barrier dysfunction such as aged skin, inflammatory bowel disease and Crohn's disease, as well as pancreatitis, or of cancer, in particular ovarian cancer.