Molecular model for VLA-4 inhibitors

A cell adhesion inhibitor of Formula GB-1

• wherein A is selected from the group consisting of aliphatic acyl optionally substituted with N-alkyl- or N-arylamido, aroyl, heterocycloyl, alkyl- or arylsulfonyl, aralkylcarbonyl optionally substituted with aryl, heterocycloalkylcarbonyl, aralkyloxycarbonyl, cycloalkylcarbonyl optionally fused with aryl, heterocycloalkoxycarbonyl, alkylaminocarbonyl, arylamino carbonyl and aralkylaminocarbonyl optionally substituted with bis(alkylsulfonyl) amino, alkoxycarbonylamino or alkenyl, alkylsulfonyl, aralkylsulfonyl, arylsulfonyl, cycloalkylsulfonyl optionally fused with aryl, heterocyclylsulfonyl, heterocyclylalkylsulfonyl, aralkoxycarbonyl, aryloxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, heterocyclylalkoxycarbonyl, mono- or di-alkylaminocarabonyl optionally substituted with aryl, (alkyl) (aralkyl) aminocarabonyl, mono- or di-aralkylaminocarbonyl, mono- or di-arylaminocarabonyl, (aryl) (alkyl) aminocarbonyl, mono- or di-cycloalkylaminocarbonyl, heterocyclylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkyl) (heterocyclyl) aminocarbonyl, (alkyl) (heterocyclylalkyl) aminocarbonyl, (aralkyl) (heterocyclyl) aminocarabonyl, (aralkyl) (heterocyclylalkyl) aminocarbonyl, alkenoyl optionally substituted with aryl, alkenylsulfonyl optionally substituted with aryl, alkynoyl optionally substituted with aryl, alkynylsulfonyl optionally substituted with aryl, cycloalkenylcarbonyl, cycloalkenylsulfonyl, cycloalkylalkanoyl, cycloalkylalkylsulfonyl, arylaroyl, biarylsulfonyl, alkoxysulfonyl, aralkoxysulfonyl, alkylaminosulfonyl, aryloxysulfonyl, arylaminosulfonyl, N-arylurea-substituted alkanoyl, N-arylurea-substituted alkylsulfonyl, cycloalkenyl-substituted carbonyl, cycloalkenyl-substituted sulfonyl, alkenoxycarbonyl optionally substituted with aryl, alkenoxysulfonyl optionally substituted with aryl, alkynoxycarbonyl optionally substituted with aryl, alkynoxysulfonyl optionally substituted with aryl, alkenyl- or alkynyl-aminocarbonyl optionally substituted with aryl, alkenyl- or alkynyl-aminosulfonyl optionally substituted with aryl, acylamino-substituted alkanoyl, acylamino-substituted alkylsulfonyl, aminocarbonyl-substituted alkanoyl, carbamoyl-substituted alkanoyl, carbamoyl-substituted alkylsulfonyl, heterocyclylalkanoyl, heterocyclylaminosulfonyl, carboxyalkyl-substituted aralkoyl, carboxyalkyl-substituted aralkylsulfonyl, oxocarbocyclyl-fused aroyl, oxocarbocyclyl-fused arylsulfonyl, heterocyclylalkanoyl, N′,N′-alkyl, arylhydrazinocarbonyl, aryloxy-substituted alkanoyl and heterocyclylalkylsulfonyl, alkenyl, alkynyl, cycloalkyl, aryl-fused cycloalkyl, cycloalkenyl, aryl, aryl-substituted alkyl (“aralkyl”), aryl-substituted alkenyl or alkynyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted cycloalkyl, biaryl, alkoxy, alkenoxy, alkynoxy, aryl-substituted alkoxy (“aralkoxy”), aryl-substituted alkenoxy or alkynoxy, alkylamino, alkenylamino or alkynylamino, aryl-substituted alkylamino, aryl-substituted alkenylamino or alkynylamino, aryloxy, arylamino, N-alkylurea-substituted alkyl, N-arylurea-substituted alkyl, alkylcarbonylamino-substituted alkyl, aminocarabonyl-substituted alkyl, heterocyclyl, heterocyclyl-substituted alkyl, heterocyclyl-substituted amino, carboxyalkyl substituted aralkyl, oxocarbocyclyl-fused aryl and heterocyclylalkyl;
• n is 1-4;
• R1 and R4 are each independently selected from the group consisting of H, aryl, aralkyl, and alkyl optionally substituted with cycloalkyl, cycloalkenyl, heterocycle, alkenyl, alkynyl, alkoxyl, hydroxyl, halogen, aralkoxy, thioalkoxy, carboxy, alkoxycarbonyl, carboxamide, amine, alkylsulfone, or alkylsulfoxide;
• R2 is selected from the group consisting of H and alkyl optionally substituted with amine, cycloalkyl, alkylsulfone, or alkylsulfoxide;
• R3 is selected from the group consisting of H and alkyl optionally substituted with aralkoxy or hydroxy;
• R1 and R2 may be taken together to form —(CR1R2)p— or —(CR1R2)qX(CR1R2)r—;
• R3 and R4 may be taken together to form —(CR1R2)m— or —(CR1R2)qX(CR1R2)r—;
• R3 and R5 may be taken together to form —(CR1R2)m—;
• X is selected from the group consisting of —CH2—, S, O, NR4, NCOR7, and NSO2R7;
• m is 3 or 4;
• p is3 or 4;
• q and r are independently 1 or 2;
• R5 is selected from the group consisting of H, hydroxy, alkyl, NH2, NHSO2R7, NHCOR7, and HCO2R7;
• R7 is selected from the group consisting of aryl aralkyl, and alkyl optionally substituted with cycloalkyl, cycloalkenyl, heterocycle, alkenyl, alkynyl, alkoxyl, hydroxyl, halogen, aralkoxy, thioalkoxy, carboxy, alkoxycarbonyl, and carboxamide;
• provided that when R3 is H, n is 2-4;
• or when n is 1, only R3 or R5 is H.