US2023048989A1PendingUtilityA1
Metap2 inhibitors and methods of treating obesity
Est. expiryApr 10, 2033(~6.7 yrs left)· nominal 20-yr term from priority
A61K 47/65A61K 38/06A61P 3/08A61K 47/58A61K 47/542A61P 3/04A61K 31/485A61P 5/50A61P 3/10A61K 31/77A61K 31/336
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Claims
Abstract
The present invention relates to modified or polymer conjugated MetAP2 inhibitors. The present invention also relates to methods of preventing, inducing, causing or increasing weight loss, treating obesity and/or treating metabolic syndrome utilizing the modified or polymer conjugated MetAP2 inhibitors. The present invention also relates to methods of improving insulin sensitivity and glycemic control, reducing insulin levels and/or improving leptin sensitivity utilizing the modified or polymer conjugated MetAP2 inhibitors.
Claims
exact text as granted — not AI-modified1 . A method for reducing insulin levels in a subject in need thereof, comprising administering at least one compound, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, selected from the group consisting of
in a therapeutically effective amount to the subject.
2 . A method for reducing insulin levels in a subject in need thereof comprising administering at least one compound, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, of the Formula
wherein, independently for each occurrence,
R 4 is H or C 1 -C 6 alkyl;
R 5 is H or C 1 -C 6 alkyl;
R 6 is C 2 -C 6 hydroxyalkyl;
Z is —NH-AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 -C(O)-L or -NH-AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 -C(O)-Q-X-Y-C(O)—W;
AA 1 is glycine, alanine, or H 2 N(CH 2 ) m CO 2 H, wherein m is 2, 3, 4 or 5;
AA 2 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine;
AA 3 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine;
AA 4 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine;
AA 5 is a bond, or glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, or asparagine;
AA 6 is a bond, or alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, or H 2 N(CH 2 ) m CO 2 H, wherein m is 2, 3, 4 or 5;
L is —OH, —O-succinimide, —O-sulfosuccinimide, alkoxy, aryloxy, acyloxy, aroyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, —NH 2 , —NH(C 2 -C 6 hydroxyalkyl), halide or perfluoroalkyloxy;
Q is NR, O, or S;
X is M-(C(R) 2 ) p -M-J-M-(C(R) 2 ) p -M-V;
M is a bond, or C(O);
J is a bond, or ((CH 2 ) q Q) r, C 5 -C 8 cycloalkyl, aryl, heteroaryl, NR, O, or S;
Y is NR, O, or S;
R is H or alkyl;
V is a bond or
R 9 is alkyl, aryl, aralkyl, or a bond; or R 9 taken together with Y forms a heterocyclic ring;
R 10 is amido or a bond;
R 11 is H or alkyl;
W is a methionine aminopeptidase-2 inhibitor moiety or alkyl;
x is in the range of 1 to about 450;
y is in the range of 1 to about 30;
n is in the range of 1 to about 50;
p is 0 to 20;
q is 2 or 3; and
r is 1, 2, 3, 4, 5, or 6;
in a therapeutically effective amount to the subject.
3 . The method of claim 2 , wherein R 4 is methyl.
4 . The method of claim 2 , wherein R 5 is methyl.
5 . The method of claim 2 , wherein R 6 is 2-hydroxypropyl.
6 . The method of claim 2 , wherein Z is —NH— AA 6 -C(O)-Q-X-Y-C(O)—W.
7 . The method of claim 6 , wherein AA 6 is glycine.
8 . The method of claim 2 , wherein Z is —NH— AA 5 -AA 6 -C(O)-Q-X-Y-C(O)—W.
9 . The method of claim 8 , wherein AA 5 is leucine and AA 6 is glycine.
10 . The method of claim 8 , wherein AA 5 is valine and AA 6 is glycine.
11 . The method of claim 8 , wherein AA 5 is phenylalanine and AA 6 is glycine.
12 . The method of claim 8 , wherein AA 5 is glycine and AA 6 is glycine.
13 . The method of claim 2 , wherein Z is —NH— AA 3 -AA 4 -AA 5 -AA 6 -C(O)-Q-X-Y-C(O)—W.
14 . The method of claim 13 , wherein AA 5 is leucine and each of AA 3 , AA 4 , or AA 6 is glycine.
15 . The method of claim 13 , wherein AA 5 is valine and each of AA 3 , AA 4 , or AA 6 is glycine.
16 . The method of claim 13 , wherein AA 5 is phenylalanine and each of AA 3 , AA 4 , or AA 6 is glycine.
17 . The method of claim 13 , wherein AA 3 is glycine, AA 4 is phenylalanine, AA 5 is leucine and AA 6 is glycine.
18 . The method of claim 13 , wherein each of AA 3 , AA 4 , AA 5 and AA 6 is glycine.
19 . The method of claim 2 , wherein -Q-X-Y is
20 . The method of claim 2 , wherein W is
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