Modulation of adipose triglyceride lipase for prevention and treatment of cachexia, loss of weight and muscle atrophy and methods of screening therefor

A method for identifying a compound that prevents, ameliorates and/or inhibits cachexia, and its associated or related disorders and conditions, comprising:

• (a) contacting a compound with a polypeptide comprising an amino acid sequence selected from the group consisting of FIGS. 7 and/or 8, and fragments thereof which is present in an in vitro cell free preparation or in a mammalian cell;
• and
• (b) measuring a compound-polypeptide property related to cachexia,
• wherein said property is the enzymatic activity of said polypeptide, the expression of said polypeptide, and/or, if said polypeptide is in an in vitro cell free preparation, the binding affinity of said compound to said polypeptide.

A method for the treatment or prevention of cachexia, or its associated or related disorders or conditions, including weight loss, muscle atrophy or wasting, fat loss, and/or reduced WAT in a subject, comprising treating the subject with an effective amount of a compound of a formula selected from the group consisting of

• (i) compound of formula (I)
• wherein:
• L1 is a bond, C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene, wherein said alkylene, said alkenylene or said alkynylene is optionally substituted with one or more groups independently selected from halogen, —CF3, —CN, —OH, —O(C1-4 alkyl), —NH2, —NH(C1-4 alkyl), or —N(C1-4 alkyl)(C1-4 alkyl), and further wherein one or more —CH2— units comprised in said alkylene, said alkenylene or said alkynylene are each optionally replaced by a group independently selected from —O—, —NH—, —N(C1-4 alkyl)-, —CO—, —CO—NH—, —NH—CO—, —S—, —SO—, or —SO2—;
• L2 is a bond, C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene, wherein said alkylene, said alkenylene or said alkynylene is optionally substituted with one or more groups independently selected from halogen, —CF3, —CN, —OH, —O(C1-4 alkyl), —NH2, —NH(C1-4 alkyl), or —N(C1-4 alkyl)(C1-4 alkyl), and further wherein one or more —CH2— units comprised in said alkylene, said alkenylene or said alkynylene are each optionally replaced by a group independently selected from —O—, —NH—, —N(C1-4 alkyl)-, —CO—, —CO—NH—, —NH—CO—, —S—, —SO—, or —SO2—;
• R1 is optionally substituted aryl or optionally substituted heteroaryl, wherein said aryl or said heteroaryl may be substituted with one or more groups independently selected from C1-4 alkyl, halogen, —CF3, —CN, —OH, —O(C1-4 alkyl), —NH2, —NH(C1-4 alkyl), or —N(C1-4 alkyl)(C1-4 alkyl);
• R2 is optionally substituted aryl or optionally substituted heteroaryl, wherein said aryl or said heteroaryl may be substituted with one or more groups independently selected from C1-4 alkyl, halogen, —CF3, —CN, —OH, —O(C1-4 alkyl), —NH2, —NH(C1-4 alkyl), or —N(C1-4 alkyl)(C1-4 alkyl);
• n is an integer of 0 to 8;
• and
• each R3 is independently selected from C1-4 alkyl, halogen, —CF3, —CN, —OH, —O(C1-4 alkyl), —NH2, —NH(C1-4 alkyl), or —N(C1-4 alkyl)(C1-4 alkyl);
• or a pharmaceutically acceptable salt, solvate or prodrug thereof,
• (ii) formula (II)
• wherein:
• R4 is selected from —OH, —O(C1-4 alkyl), —NH2, —NH(C1-4 alkyl), —N(C1-4 alkyl)(C1-4 alkyl), —SH, or —S(C1-4 alkyl);
• R5 is selected from —OH or —O(C1-4 alkyl);
• R6 is —CF3 or CN;
• m is an integer of 0 to 5;
• and
• each R7 is independently selected from C1-4 alkyl, halogen, —CF3, —CN, —OH, —O(C1-4 alkyl), —NH2, —NH(C1-4 alkyl), or —N(C1-4 alkyl)(C1-4 alkyl);
• or a pharmaceutically acceptable salt, solvate or prodrug thereof;
• (iii) formula (III)
• wherein:
• R8 is selected from —OH, —O(C1-4 alkyl), —NH2, —NH(C1-4 alkyl), —N(C1-4 alkyl)(C1-4 alkyl), —SH, or —S(C1-4 alkyl);
• R9 and R10 are each independently selected from C1-4 alkyl, halogen, —CN, —OH, —O(C1-4 alkyl), —NH2, —NH(C1-4 alkyl), or —N(C1-4 alkyl)(C1-4 alkyl);
• p is an integer of 0 to 5;
• and
• each R11 is independently selected from C1-4 alkyl, halogen, —CF3, —CN, —OH, —O(C1-4 alkyl), —NH2, —NH(C1-4 alkyl), or —N(C1-4 alkyl)(C1-4 alkyl);
• or a pharmaceutically acceptable salt, solvate or prodrug thereof, or
• (iv) formula (IV)
• wherein:
• L3 is a bond, C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene, wherein said alkylene, said alkenylene or said alkynylene is optionally substituted with one or more groups independently selected from halogen, —CF3, —CN, —OH, —O(C1-4 alkyl), —NH2, —NH(C1-4 alkyl), or —N(C1-4 alkyl)(C1-4 alkyl), and further wherein one or more —CH2— units comprised in said alkylene, said alkenylene or said alkynylene are each optionally replaced by a group independently selected from —O—, —NH—, —N(C1-4 alkyl)-, —CO—, —CO—NH—, —NH—CO—, —S—, —SO—, or —SO2−;
• and
• R12 is optionally substituted aryl or optionally substituted heteroaryl, wherein said aryl or said heteroaryl may be substituted with one or more groups independently selected from C1-4 alkyl, halogen, —CF3, —CN, —OH, —O(C1-4 alkyl), —NH2, —NH(C1-4 alkyl), or —N(C1-4 alkyl)(C1-4 alkyl);
• or a pharmaceutically acceptable salt, solvate or prodrug thereof.