US 12,263,202 B2
Method of treating melanocortin-4 receptor pathway-associated disorders
Leonardus H. T. Van Der Ploeg, Newton, MA (US); and Bart Henderson, Belmont, MA (US)
Assigned to RHYTHM PHARMACEUTICALS, INC., Boston, MA (US)
Filed by CHARITÉ—UNIVERSITÄTSMEDIZIN BERLIN, Berlin (DE); and RHYTHM PHARMACEUTICALS, INC., Boston, MA (US)
Filed on Feb. 9, 2021, as Appl. No. 17/171,563.
Application 17/171,563 is a continuation of application No. 15/764,725, granted, now 10,960,046, issued on Mar. 30, 2021, previously published as PCT/US2016/054457, filed on Sep. 29, 2016.
Claims priority of provisional application 62/235,003, filed on Sep. 30, 2015.
Prior Publication US 2021/0169970 A1, Jun. 10, 2021
Int. Cl. A61K 38/00 (2006.01); A61K 9/00 (2006.01); A61K 38/12 (2006.01); A61P 3/04 (2006.01); A61P 3/10 (2006.01); C07K 7/06 (2006.01); C07K 7/54 (2006.01); C07K 14/685 (2006.01); C07K 14/72 (2006.01)
CPC A61K 38/12 (2013.01) [A61K 9/0019 (2013.01); A61P 3/04 (2018.01); A61P 3/10 (2018.01); C07K 7/06 (2013.01); C07K 7/54 (2013.01); C07K 14/685 (2013.01); C07K 14/723 (2013.01)] 21 Claims
 
1. A method of treating a disorder in a subject in need thereof, comprising:
administering an agonist of the melanocortin-4 receptor (MC4R) at a daily dosage of about 0.1 mg to about 10 mg,
wherein the disorder is characterized by one or more mutations in a gene associated with Bardet-Biedl syndrome,
wherein the agonist is a MC4R agonist having a structure of Formula (I)
(R2R3)-A1-c(A2-A3-A4-A5-A6-A7-A8-A9)-A10-R1  (I),
wherein:
A1 is Acc, HN—(CH2)m—C(O), L- or D-amino acid, or deleted;
A2 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp, or Glu;
A3 is Gly, Ala, β-Ala, Gaba, Aib, D-amino acid, or deleted;
A4 is H is, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-Thi, or (X1, X2, X3, X4, X5)Phe;
A5 is D-Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal, D-(X1, X2, X3, X4, X5)Phe, L-Phe or D-(Et)Tyr;
A6 is Arg, hArg, Dab, Dap, Lys, Orn, or HN—CH((CH2)n—N(R4R5))—C(O);
A7 is Trp, 1-Nal, 2-Nal, Bal, Bip, D-Trp, D-2-Nal, D-Bal or D-Bip;
A8 is Gly, D-Ala, Acc, Ala, 13-Ala, Gaba, Apn, Ahx, Aha, HN—(CH2)s—C(O), or deleted;
A9 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Dab, Dap, Orn, or Lys;
A10 is Acc, HN—(CH2)r—C(O), L- or D-amino acid, or deleted;
R1 is OH or NH2;
each of R2 and R3 is, independently for each occurrence, selected from the group consisting of H, (C1-C30)alkyl, (C1-C30)heteroalkyl, (C1-C30)acyl, (C2-C30)alkenyl, (C2-C30)alkynyl, aryl(C1-C30)alkyl, aryl(C1-C30)acyl, substituted (C1-C30)alkyl, substituted (C1-C30)heteroalkyl, substituted (C1-C30)acyl, substituted (C2-C30)alkenyl, substituted (C2-C30)alkynyl, substituted aryl(C1-C30)alkyl, and substituted aryl(C1-C30)acyl;
each of R4 and R5 is, independently for each occurrence, H, (C1-C40)alkyl, (C1-C40)heteroalkyl, (C1-C40)acyl, (C2-C40)alkenyl, (C2-C40)alkynyl, aryl(C1-C40)alkyl, aryl(C1-C40)acyl, substituted (C1-C40)alkyl, substituted (C1-C40)heteroalkyl, substituted (C1-C40)acyl, substituted (C2-C40)alkenyl, substituted (C2-C40)alkynyl, substituted aryl(C1-C40)alkyl, substituted aryl(C1-C40)acyl, (C1-C40)alkylsulfonyl, or —C(NH)—NH2;
m is, independently for each occurrence, 1, 2, 3, 4, 5, 6 or 7;
n is, independently for each occurrence, 1, 2, 3, 4 or 5;
s is, independently for each occurrence, 1, 2, 3, 4, 5, 6, or 7;
t is, independently for each occurrence, 1, 2, 3, 4, 5, 6, or 7;
X′, X2, X3, X4, and X8 each is, independently for each occurrence, H, F, Cl, Br, I, (C1-10)alkyl, substituted (C1-10)alkyl, (C2-10)alkenyl, substituted (C2-10)alkenyl, (C2-10)alkynyl, substituted (C2-10)alkynyl, aryl, substituted aryl, OH, NH2, NO2, or CN.