Method of treating melanocortin-4 receptor pathway-associated disorders

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 (e.g., 0.1 mg+/−5%) to about 10 mg (e.g., 10 mg+/−5%),
• wherein the disorder is chosen from:
• (i) Prader Willi Syndrome (PWS);
• (ii) a disorder characterized by one or more mutations (e.g., loss of function mutations) in the POMC gene;
• (iii) a disorder characterized by one or more mutations (e.g., loss of function mutations) in the PCSK1 gene;
• (iv) a disorder characterized by one or more mutations (e.g., loss of function mutations) in the MAGEL2 gene;
• (v) a disorder characterized by one or more mutations (e.g., loss of function mutations) in the leptin receptor gene;
• (vi) a disorder characterized by one or more mutations (e.g., loss of function mutations) in the leptin gene;
• (vii) a disorder characterized by one or more mutations (e.g., loss of function mutations) in the 5-HT2c receptor gene;
• (viii) a disorder characterized by one or more mutations (e.g., loss of function mutations) in the nescient helix loop helix 2 (NhHL2) gene;
• (ix) a disorder characterized by one or more mutations (e.g., loss of function mutations) in the pro-hormone convertase gene;
• (x) a disorder characterized by one or more mutations (e.g., loss of function mutations) in the carboxypeptidase E (CPE) gene;
• (xi) a disorder characterized by one or more mutations (e.g., loss of function mutations) in the single-minded 1 (SIM1) gene;
• (xii) a disorder characterized by a hypermethylated POMC gene (e.g., hypermethylated at a POMC intron, e.g., at a CpG island of the POMC gene, e.g., comprising one or more methylated cytosines, e.g., a 5′ methyl cytosine);
• or
• (xiii) a disorder characterized by a defect in the POMC-MC4R pathway other than:
• (a) a heterozygous POMC mutation characterized by the presence of one functional POMC allele and one non-functional POMC allele,
• (b) a heterozygous leptin mutation characterized by the presence of one functional leptin allele and one non-functional leptin allele,
• (c) a melanocortin-4 receptor (MC4R) mutation (e.g., loss of function mutation),
• (d) a pro-hormone convertase mutation (e.g., loss of function mutation);
• (e) a mutation in a gene associated with Bardet-Biedl syndrome (e.g., a mutation in BBS1-BBS20);
• or
• (f) a mutation in a gene associated with Alström syndrome,
• wherein the agonist is a MC4R agonist described herein, e.g., the agonist is
• (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)t—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.

A method of treating a disorder chosen from:

• (i) a disorder characterized by one or more mutations (e.g., loss of function mutations) in the PCSK1 gene;
• (ii) a disorder characterized by one or more mutations (e.g., loss of function mutations) in the MAGEL2 gene;
• (iii) a disorder characterized by one or more mutations (e.g., loss of function mutations) in the leptin receptor gene;
• (iv) a disorder characterized by one or more mutations (e.g., loss of function mutations) in the 5-HT2c receptor gene;
• (v) a disorder characterized by one or more mutations (e.g., loss of function mutations) in the nescient helix loop helix 2 (NhHL2) gene;
• (vi) a disorder characterized by one or more mutations (e.g., loss of function mutations) in the carboxypeptidase E (CPE) gene;
• (vii) a disorder characterized by one or more mutations (e.g., loss of function mutations) in the single-minded 1 (SIM1) gene;
• (viii) a disorder characterized by a hypermethylated POMC gene (e.g., hypermethylated at a POMC intron, e.g., at a CpG island of the POMC gene, e.g., comprising a methylated cytosine, e.g., a 5′ methyl cytosine);
• (ix) a disorder characterized by a defect in the POMC-MC4R pathway other than:
• (a) a POMC mutation, e.g., a heterozygous POMC mutation characterized by the presence of one functional POMC allele and one non-functional POMC allele,
• (b) a leptin mutation, e.g., a heterozygous leptin mutation characterized by the presence of one functional leptin allele and one non-functional leptin allele,
• (c) a melanocortin-4 receptor (MC4R) mutation, or
• (d) a prohormone convertase mutation;
• (x) a disorder characterized by a homozygous POMC mutation (e.g., loss of function mutation), e.g., characterized by a POMC null genotype;
• (xi) a disorder characterized by a compound heterozygous POMC mutation (e.g., characterized by the presence of two non-functional alleles) e.g., characterized by a POMC null genotype;
• (xii) a disorder characterized by a homozygous leptin mutation (e.g., loss of function mutation), e.g., characterized by a leptin null genotype;
• (xiii) a disorder characterized by a compound heterozygous leptin mutation (e.g., characterized by the presence of two non-functional alleles) e.g., characterized by a leptin null genotype,
• (xiv) a disorder characterized by a mutation in a gene associated with Bardet-Biedl syndrome (e.g., a mutation in BBS1-BBS20);
• or
• (xv) a disorder characterized by a a mutation in a gene associated with Alstrom syndrome,
• in a subject in need thereof, comprising administering an agonist of the melanocortin-4 receptor (MC4R),
• wherein the agonist is a MC4R agonist described herein, e.g., the agonist is
• (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.