Methods for treating disorders associated with the melanocortin-4 receptor pathway

Abstract

A method for treating disorders associated with the melanocortin-4 receptor pathway is provided. The present disclosure relates to methods of treating disorders such as obesity or obesity-related conditions (e.g., bulimia) in a subject using a melanocortin-4 receptor (MC4R) agonist. In certain embodiments, the methods described herein include ameliorating or improving clinical symptoms or indications associated with a disorder described herein, such as obesity, type 2 diabetes, pre-diabetic conditions, hemoglobin A1C (Hb1Ac) blood levels greater than 6%, hyperinsulinemia, hyperlipidemia, insulin insensitivity, or glucose intolerance; delaying, inhibiting, or preventing the progression of obesity and / or obesity-related indications; or partially or completely delaying, inhibiting, or preventing the onset or progression of obesity or obesity-related indications.

Description

[Technical Field]

[0001] Background of the Invention The melanocortin 4 receptor (MC4R) is a heterotrimeric G protein-coupled receptor that transduces signals by activating adenylate cyclase-containing second messenger systems. MC4R, which is expressed in the hypothalamic nucleus and other neural and non-neuronal tissues and regulates feeding behavior and energy homeostasis, integrates agonist (anorexigenic) signals provided by α-melanocyte-stimulating hormone (α-MSH) with antagonist (orexic) signals provided by agouti-related peptide (AGPR). MC4R signals regulate feeding behavior via second effector neurons. Summary of the Invention [Means for solving the problem]

[0002] The present invention is based, in part, on the discovery of novel MC4R agonists. These MC4R agonists are useful, for example, in treating obesity-related disorders. Obesity disorders include, for example, polygenic and monogenic obesity disorders, including morbid obesity. Treatment of obesity results in weight loss primarily due to a reduction in body fat mass, which is often attributed to medications associated with reduced appetite and increased or normalized energy expenditure. Improvement of comorbidities may include reduced insulin resistance through reduced blood pressure and / or heart rate, and improved cardiovascular parameters.

[0003] Thus, in one aspect, the invention features a compound of Formula I or II (or a pharmaceutically acceptable salt thereof): Formula I has the structure set forth in the following formula: [ka] During the ceremony, Aaa, Bbb = Cys, hCys, Pen capable of establishing disulfide bridges; or It is selected from Glu, Asp, Lys, Om, Dpr, Dbu, which are capable of establishing a lactam bridge. Xxx=Asn, Gln, Ser, Thr Yyy = Lys, Arg, D-Lys, D-Arg A1=H, Ac A2=OH, NH2 Ac is acyl (eg, acetyl).

[0004] In embodiments, the MC4R agonist is a compound of the following structure (Formula II) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, Xxx is Asn, Gln, Ser, or Thr, A1 is H or Ac; A2 is OH or NH2, and Yyy is Lys, Arg, D-Lys, or D-Arg.

[0005] In embodiments, the MC4R agonist is selected from one or more of the following compounds (or pharmaceutically acceptable salts thereof): 001554C: Ac-Arg-(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 1) 001555C: Ac-Arg-(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 2), 001556C: Ac-Arg-(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 3), 001574C: Ac-Arg-(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 4), 001576C: Ac-Arg-(Glu-Gln-D-Phe-Arg-Trp-Apr)-NH2 (SEQ ID NO: 5), Ac-Arg-(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 6), H-Arg-(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 7), H-Arg-(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 8), Ac-D-Arg-(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 9), HD-Arg-(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 10), Ac-D-Arg-(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 11), HD-Arg-(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 12), Ac-Lys-(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 13), Ac-Lys-(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 14), H-Lys-(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 15), H-Lys-(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 16), Ac-D-Lys-(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 17), HD-Lys-(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 18), Ac-D-Lys-(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 19), HD-Lys-(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 20), Ac-Arg-(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 21), H-Arg-(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 22), H-Arg-(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 23), Ac-D-Arg-(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 24), HD-Arg-(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 25), Ac-D-Arg-(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 26), HD-Arg-(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 27), Ac-Lys-(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 28), Ac-Lys-(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 29), H-Lys-(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 30), H-Lys-(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 31), Ac-D-Lys-(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 32), HD-Lys-(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 33), Ac-D-Lys-(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 34), HD-Lys-(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 35), Ac-Arg-(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 36), H-Arg-(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 37), H-Arg-(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 38), Ac-D-Arg-(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 39), HD-Arg-(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 40) Ac-D-Arg-(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 41), HD-Arg-(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 42), Ac-Lys-(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 43), Ac-Lys-(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 44), H-Lys-(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 45), H-Lys-(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 46), Ac-D-Lys-(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 47), HD-Lys-(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 48), Ac-D-Lys-(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 49), HD-Lys-(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 50), Ac-Arg-(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 51), H-Arg-(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 52), H-Arg-(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 53), Ac-D-Arg-(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 54), HD-Arg-(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 55), Ac-D-Arg-(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 56), HD-Arg-(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 57), Ac-Lys-(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 58), Ac-Lys-(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 59), H-Lys-(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 60), H-Lys-(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 61), Ac-D-Lys-(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 62), HD-Lys-(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 63), Ac-D-Lys-(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 64) or HD-Lys-(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 65).

[0006] In another aspect, the present invention provides a method of eliciting an agonist effect from a melanocortin receptor in a subject in need thereof, comprising administering to said subject an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof.

[0007] In another aspect, the present invention provides a method of treating a condition or disorder (e.g., an obesity-related condition) by administering a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof.

[0008] In another aspect, the present invention provides a method for treating a metabolic disease or medical condition associated with weight gain (e.g., obesity, eating disorders, Prader-Willi syndrome, etc.) by administering an effective amount of a compound of Formula (I) or Formula (II) as defined above, or a pharmaceutically acceptable salt thereof. Without being bound by theory, it is believed that the anti-obesity effect of the agonist derives from melanocortin receptor activity. In a further aspect of the above method, the disease or condition being treated is obesity. In yet a further aspect of the above method, the disease or condition being treated is an eating disorder.

[0009] In another aspect, the present invention provides a method for reducing food intake, reducing body weight, or a combination thereof, by administering an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the present invention provides a method for reducing food intake, reducing body weight, or a combination thereof, by administering an effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, to elicit an agonist or antagonist effect at a melanocortin receptor.

[0010] In another aspect, the present invention provides a method for reducing appetite without loss of body weight by administering an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof. In another aspect, the present invention provides a method for reducing food consumption and simultaneously reducing body weight by administering an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof. In another aspect, the present invention provides a method for increasing or normalizing energy expenditure (e.g., promoting and / or achieving weight loss) by reducing body fat mass in a subject.

[0011] In embodiments, the condition or disorder is obesity (e.g., Prader-Willi syndrome). In embodiments, the agonist is administered to reduce food intake or reduce weight in a subject in need thereof.

[0012] In certain embodiments, the methods described herein include ameliorating or improving clinical symptoms or indications associated with a disorder described herein, such as, for example, obesity, type II diabetes, pre-diabetic conditions, hemoglobin A1C (Hb1Ac) blood levels greater than 6%, hyperinsulinemia, hyperlipidemia, insulin insensitivity or glucose intolerance; delaying, inhibiting, or preventing the progression of obesity and / or obesity-related indications; or partially or completely delaying, inhibiting, or preventing the onset or progression of obesity or obesity-related indications.

[0013] In embodiments, the method includes administering to a subject a unit dosage of an agonist suitable for injection (e.g., subcutaneous injection), for example, by administering the compound orally, via a suppository, by absorption through the skin, intranasally, or sublingually.

[0014] In some embodiments, the daily dosage is 0.1 mg to 10 mg, in some embodiments, the daily dosage is about 0.1 mg to about 7.5 mg, in some embodiments, the daily dosage is about 0.1 mg to about 5 mg, in some embodiments, the daily dosage is about 0.1 mg to about 2.5 mg, in some embodiments, the daily dosage is about 0.1 mg to about 2 mg, in some embodiments, the daily dosage is about 0.1 mg to about 1 mg, in some embodiments, the daily dosage is about 0.2 mg to about 10 mg, in some embodiments, the daily dosage is about 0.2 mg to about 7.5 mg, in some embodiments, the daily dosage is about 0.2 mg to about 5 mg, in some embodiments, the daily dosage is about 0.2 mg to about 2.5 mg, in some embodiments, the daily dosage is about 0.2 mg to about 2 mg. In some embodiments, the daily dosage may be about 0.2 mg to about 1.5 mg, in some embodiments, the daily dosage may be about 0.2 mg to about 1 mg, in some embodiments, the daily dosage may be about 0.3 mg to about 10 mg, in some embodiments, the daily dosage may be about 0.3 mg to about 7.5 mg, in some embodiments, the daily dosage may be about 0.3 mg to about 5 mg, in some embodiments, the daily dosage may be about 0.3 mg to about 2.5 mg, in some embodiments, the daily dosage may be about 0.3 mg to about 2 mg, in some embodiments, the daily dosage may be about 0.3 mg to about 1.5 mg, in some embodiments, the daily dosage may be about 0.3 mg to about 1 mg, and in some embodiments, the daily dosage may be about 0.25 mg (e.g., 0.25 mg) to about 0.5 mg (e.g., 0.5 mg).In embodiments, the daily dosage may be about 0.5 mg (e.g., 0.5 mg) to about 0.75 mg (e.g., 0.75 mg), in embodiments, the daily dosage may be about 0.25 mg (e.g., 0.25 mg), in embodiments, the daily dosage may be about 0.5 mg (e.g., 0.5 mg), in embodiments, the daily dosage may be about 0.75 mg (e.g., 0.75 mg) to about 1.25 mg (1.25 mg), in embodiments, the daily dosage may be about 1 mg (e.g., 1 mg), in embodiments, the daily dosage may be about 1.25 mg (e.g., 1.25 mg) to about 2 mg (e.g., 2 mg), in embodiments, the daily dosage may be about 1.5 mg (e.g., 1.5 mg), in embodiments, the daily dosage may be about 2 mg (e.g., 2 mg).

[0015] In embodiments, the method comprises administering to the subject a unit dosage of the agonist suitable for injection (eg, subcutaneous injection).

[0016] In embodiments, the unit dosage comprises about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, or 2 mg of agonist.

[0017] In embodiments, the unit dosage is disposed in a delivery device, for example, a syringe (e.g., a pre-filled syringe), an implantable device, a needleless hypodermic injection device, an infusion pump (e.g., an implantable infusion pump), or an osmotic delivery system.

[0018] In embodiments, the agonist is administered subcutaneously, for example by subcutaneous injection.

[0019] In embodiments, the agonist is administered systemically, e.g., orally or via other routes, in a dose range of, e.g., 0.1 mg to 100 mg, 1 mg to 500 mg, or 10 mg to 1000 mg, such that an effective therapeutic concentration is achieved.

[0020] In embodiments, the agonist is administered systemically, for example, orally or via other routes, in a dose range of 0.1 mg to 100 mg, 1 mg to 500 mg, 10 mg to 1000 mg, such that an effective therapeutic concentration is achieved.

[0021] In embodiments, the agonist is administered daily for at least 3 weeks, e.g., at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 weeks or more, or for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months or more, or for at least 1, 2, 3, 4, or more years.

[0022] In an embodiment, the subject is obese (eg, severely obese).

[0023] In an embodiment, the subject has early-onset severe obesity.

[0024] In an embodiment, the subject is in a hyperphagic state.

[0025] In embodiments, the subject's body mass index (BMI) prior to administration of the agonist (e.g., at the time the agonist is prescribed or first administered) is 25 kg / m 2 Over (e.g., 25 kg / m 2More than 30kg / m 2 More than 31kg / m 2 More than 32kg / m 2 More than 33kg / m 2 More than 34kg / m 2 More than 35kg / m 2 More than 36kg / m 2 More than 37kg / m 2 More than 38kg / m 2 More than 39kg / m 2 More than 40kg / m 2 More than 41kg / m 2 More than 42kg / m 2 More than 43kg / m 2 More than 44kg / m 2 More than 45kg / m 2 More than 46kg / m 2 More than 47kg / m 2 More than 48kg / m 2 More than 49kg / m 2 More than 50kg / m 2 (greater than or equal to the value).

[0026] In embodiments, the subject's body mass index (BMI) prior to administration of the agonist (e.g., at the time the agonist is prescribed or first administered) is 35 kg / m 2 Over (e.g., 36 kg / m 2 More than 37kg / m 2 More than 38kg / m 2 More than 39kg / m 2 More than 40kg / m 2 More than 41kg / m 2 More than 42kg / m 2 More than 43kg / m 2 More than 44kg / m 2 More than 45kg / m 2 More than 46kg / m 2 More than 47kg / m 2 More than 48kg / m 2 More than 49kg / m 2 More than 50kg / m 2 (greater than or equal to the value).

[0027] In embodiments, the subject's body mass index (BMI) prior to administration of the agonist (e.g., at the time the agonist is prescribed or first administered) is 40 kg / m 2 Over (e.g., 41 kg / m 2 More than 42kg / m 2 More than 43kg / m 2 More than 44kg / m 2 More than 45kg / m 2 More than 46kg / m 2 More than 47kg / m 2 More than 48kg / m 2 More than 49kg / m 2 More than 50kg / m 2 More than 51kg / m 2 More than 52kg / m 2 More than 53kg / m 2 More than 54kg / m 2 More than 55kg / m 2 (greater than or equal to the value).

[0028] In embodiments, the subject's body mass index (BMI) prior to administration of the agonist (e.g., at the time the agonist is prescribed or first administered) is 45 kg / m 2 Over (e.g., 46 kg / m 2 More than 47kg / m 2 More than 48kg / m 2 More than 49kg / m 2 More than 50kg / m 2 More than 51kg / m 2 More than 52kg / m 2 More than 53kg / m 2 More than 54kg / m 2 More than 55kg / m 2 (greater than or equal to the value).

[0029] In embodiments, the subject's BMI prior to administration of the agonist (eg, at the time the agonist is prescribed or first administered) is above the 85th to 95th percentile.

[0030] In embodiments, the subject has failed one or more previous therapies, e.g., exercise, dietary therapy, surgery such as banding gastroplasty (e.g., vertical banding gastroplasty) or bariatric surgery, or behavioral therapy, prior to administering the agonist (e.g., at the time the agonist is prescribed or at the time of the first administration).

[0031] In embodiments, the subject's weight is reduced after administration of the agonist compared to before administration of the agonist.

[0032] In embodiments, administration of the agonist reduces a subject's weight by about 0.5 kg to 3 kg after 1 week of treatment, or about 1 kg to 6 kg after 2 weeks of treatment, or about 2 kg to 12 kg after 4 weeks of treatment, or about 4 kg to 24 kg after 8 weeks of treatment, or about 8 kg to 48 kg after 16 weeks of treatment, compared to the subject's weight before treatment.

[0033] In embodiments, the subject's weight is reduced by administering the agonist at a rate of about 0.5-1 kg / week, 1-2 kg / week (e.g., about 2 kg / week), for example, over 1-2 weeks of treatment or longer, over 2-4 weeks of treatment or longer, over 4-8 weeks of treatment or longer, over 8-16 weeks of treatment or longer, over 16-32 weeks or longer, or over 32-64 weeks or longer.

[0034] In embodiments, the subject's hunger level is reduced (e.g., the score on the Likert Hunger Scale is reduced, e.g., by at least a 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 point decrease) by administration of the agonist compared to the subject's hunger level before treatment, and the subject's sense of hunger disappears (e.g., a Likert Hunger Scale score of 0), e.g., after 1-2 weeks or longer of treatment, after 2-4 weeks or longer of treatment, after 4-8 weeks or longer of treatment, or after 8-16 weeks or longer of treatment.

[0035] In embodiments, administration of the agonist results in no detectable / significant reduction in the subject's resting energy expenditure (REE), e.g., over a 24 hour, 1 week or 30 day period, or longer, compared to, e.g., a control REE (e.g., the subject's REE before treatment, or a predefined REE, e.g., expressed as REE / kg of lean body mass in a subject with a similar pre-treatment BMI).

[0036] In embodiments, the resting energy expenditure (REE) in a subject is increased by administering the agonist, e.g., over a 24 hour period, a week, or 30 days or longer period, e.g., compared to a control REE (e.g., the REE of the subject before treatment, or a predefined REE, e.g., the REE in a subject with a similar pre-treatment BMI when expressed as REE / kg of lean body mass after a similar level of weight loss is achieved by fasting).

[0037] In embodiments, the subject's food intake is reduced by administration of the agonist, for example, when food intake is measured as daily food intake or food intake over a 24-hour or weekly period, compared to a control (e.g., the subject's food intake before treatment).

[0038] In embodiments, food intake is reduced by administering an agonist by at least 100 kcal, e.g., at least 100 kcal, 125 kcal, 150 kcal, 175 kcal, 200 kcal, 225 kcal, 250 kcal, 275 kcal, 300 kcal, 325 kcal, 350 kcal, 375 kcal, 400 kcal, 425 kcal, 450 kcal, 475 kcal, 500 kcal, 525 kcal, 550 kcal, 575 kcal, 600 kcal, 1000 kcal, or more, compared to a control (e.g., the subject's food intake before treatment, or a pre-defined food intake level), e.g., when food intake is measured as daily food intake or food intake over a 24-hour or weekly period.

[0039] In an embodiment, food intake is reduced by at least 5 kcal / kg / day, e.g., 5 kcal / kg, 10 kcal / kg, 20 kcal / kg, 30 kcal / kg, 40 kcal / kg, 50 kcal / kg, 60 kcal / kg, 70 kcal / kg, 80 kcal / kg / day, or 90 kcal / kg / day or more, by administering the agonist. In an embodiment, the reduction in food intake is relative to the baseline food intake. In an embodiment, for example, for a pediatric subject about 1 year old, the baseline food intake is at least 100 kcal / kg / day. In an embodiment, for example, for a pediatric subject, such as a late adolescent, the baseline food intake is at least 40 kcal / kg / day.

[0040] In embodiments, administration of the agonist results in a decrease in the subject's waist circumference when measured 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks or longer after initiation of treatment, compared to a control (e.g., the subject's waist circumference before treatment).

[0041] In embodiments, administration of the agonist results in a reduction in the subject's waist circumference of at least 2 cm (e.g., at least 2 cm, 3 cm, 4 cm, 5 cm, 6 cm, 7 cm, 8 cm, 9 cm, 10 cm or more) compared to a control (e.g., the subject's waist circumference before treatment) when measured 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks or longer after initiation of treatment.

[0042] In embodiments, administration of an agonist does not detectably increase a subject's blood pressure (e.g., diastolic and / or systolic pressure) compared to the subject's blood pressure before treatment when measured 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks or longer after initiation of treatment.

[0043] In embodiments, administration of the agonist reduces the subject's blood pressure (e.g., diastolic and / or systolic blood pressure) when measured 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks or longer after initiation of treatment, compared to the subject's blood pressure before treatment.

[0044] In embodiments, administration of the agonist reduces the subject's systolic blood pressure by at least 1-3 mmHg (e.g., at least 1 mmHg, 2 mmHg, 3 mmHg, 3.5 mmHg, 4 mmHg, 4.5 mmHg, 5 mmHg, 5.5 mmHg, 6 mmHg, 6.5 mmHg, 7 mmHg, or more) compared to the subject's blood pressure before treatment when measured 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, or longer after initiation of treatment.

[0045] In embodiments, administration of the agonist results in a reduction in the subject's diastolic blood pressure of at least 4 mmHg (e.g., at least 4 mmHg, 7 mmHg, 7.5 mmHg, 8 mmHg, 8.5 mmHg, 9 mmHg, 9.5 mmHg, 10 mmHg or more) compared to the subject's blood pressure before treatment when measured 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks or longer after initiation of treatment.

[0046] In embodiments, the subject is a mammal (eg, a human).

[0047] In certain embodiments, the agonist is administered via an implantable device, a needleless hypodermic injection device, an infusion pump (eg, an implantable infusion pump), or an osmotic delivery system.

[0048] In embodiments, the agonist is administered subcutaneously, for example by subcutaneous injection.

[0049] In some embodiments, the agonists provided herein are in unit dosage amounts described herein, wherein the unit dosage amount contains 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, or 5 mg of agonist.

[0050] In an embodiment, the unit dosage contains 0.5 mg of the agonist.

[0051] In an embodiment, the unit dosage contains 1.0 mg of agonist.

[0052] In an embodiment, the unit dosage contains 1.5 mg of the agonist.

[0053] In embodiments, the unit dosage is suitable for injection (eg, subcutaneous injection).

[0054] In embodiments, the unit dosage is placed in a delivery device suitable for injection (eg, subcutaneous injection).

[0055] In embodiments, the unit dosage is disposed in a syringe suitable for injection (eg, subcutaneous injection), or a pen-type injector.

[0056] According to any of the methods described herein, in embodiments, amelioration of symptoms includes one or more of the following: (a) weight loss; (b) reduction in waist circumference; (c) reduced hunger levels; (d) reduced food intake levels; (e) a decrease or lack of increase in resting energy expenditure; (f) decreased insulin resistance; (g) a reduction in sleep apnea; or (h) Reduction of symptoms associated with metabolic syndrome.

[0057] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials used in practicing or testing the present invention may be similar or equivalent to those described herein, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. Additionally, the materials, methods, and examples are for illustrative purposes only and are not intended to be limiting. Headings, subheadings, or numbered or lettered elements (a), (b), (i), etc. are presented solely for ease of reading. The use of headings or numbered or lettered elements in this document does not require the steps or elements to be performed in alphabetical order or that the steps or elements be necessarily discrete from one another. Other features, aims, and advantages of the present invention will become apparent from the specification and drawings, and from the claims. DETAILED DESCRIPTION OF THE INVENTION

[0058] definition As used herein, "about" and "approximately" generally refer to an acceptable degree of error for the quantity measured, given the nature or precision of the measurement. Exemplary degrees of error are within 20 percent (%), typically within 10%, and more typically within 5% of a given value or range of values.

[0059] As used herein, the terms "acquire" or "acquiring" refer to gaining ownership of a physical entity or value (e.g., a numerical value, or knowledge about a genotype or nucleic acid or polypeptide (e.g., knowledge about a sequence or mutational state)) either "by directly obtaining" or "by indirectly obtaining" the physical entity, value, or knowledge. "Directly obtaining" means performing a physical process (e.g., performing a synthetic or analytical method) to obtain the physical entity, value, or knowledge. "Indirectly obtaining" refers to receiving a physical entity, value, or knowledge from another party or source (e.g., a third-party laboratory that directly obtains the physical entity, value, or knowledge). Directly obtaining a physical entity includes performing a process that involves a physical change in a physical substance, such as a starting material. Exemplary changes include creating a physical entity from two or more starting materials, shearing or fragmenting a substance, separating or purifying a substance, combining two or more separate entities to produce a mixture, and performing a chemical reaction that involves breaking or forming covalent or non-covalent bonds. Directly obtaining value or knowledge includes performing a process that involves a physical change in a sample or another substance. Examples include performing analytical processes (sometimes referred to herein as "physical analyses") that involve physical changes in substances such as samples, specimens, or reagents; performing analytical methods (e.g., methods that include any one or more of the steps described below). Separating or purifying one substance (such as an analyte or a fragment or other derivative thereof) from another substance; combining the analyte or fragment or other derivative thereof with another substance (e.g., a buffer, solvent, or reactant); Alternatively, modifying the structure of the analyte or fragment or other derivative thereof, for example by breaking or forming a covalent or non-covalent bond between a first and second atom of the analyte, or by modifying the structure of the reagent or fragment or other derivative thereof (e.g., breaking or forming a covalent or non-covalent bond between a first and second atom of the reagent).

[0060] As used herein, the term "obesity" refers to a subject whose body mass index (BMI) is within the range defined by the Center for Disease Control as "obese" (see, e.g., URL.cdc.gov / obesity / defining.html and www.cdc.gov / obesity / childhood / defining.html (last accessed August 19, 2015)), or as defined by the "Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults" established by the National Institutes of Health. BMI is obtained by dividing a subject's weight (e.g., in kilograms (kg)) by the square of the subject's height (e.g., in meters (m)). For example, a BMI of 30 kg / m in an adult is considered obese. 2 or higher is considered obese. For example, an adult with a BMI of 25.0 to 29.9 kg / m 2 is considered overweight; in adults, BMI is 18.5 to 24.9 kg / m 2 is considered within the normal or healthy weight range; in adults, a BMI of 18.5 kg / m 2A person is considered underweight if they are underweight. For example, an adult who is 5 feet 9 inches tall and weighs 203 pounds or more is considered obese. Obesity in children and teens refers to a BMI at or above the 85th-95th percentile for children and teens of the same age and sex.

[0061] A subject who is "severely obese" or has "severe obesity" is defined as a subject whose BMI is 35 kg / m 2 or more (e.g., 40 kg / m 2 ) or a value exceeding that. For example, a subject with severe obesity has an ideal body weight (normal weight, healthy weight) that exceeds 100%.

[0062] As used herein, "early onset," e.g., with respect to early-onset obesity, refers to the onset of a disorder (e.g., the first occurrence of one or more symptoms in a disorder such as obesity described herein) occurring in a subject before adulthood (e.g., during childhood, when the subject is under 18 years of age, or earlier (e.g., at or below the age of 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 year of age), or during adolescence (e.g., when a child is under 12 years of age, or when a child is under 6 years of age, etc.).

[0063] As used herein, the term "metabolic syndrome" refers to a group of conditions that occur together and increase the risk of coronary artery disease, stroke, and type II diabetes. According to the American Heart Association and the National Heart, Lung, and Blood Institute, metabolic syndrome (also known as Syndrome X) is present when a subject has three or more of the following symptoms: 1) blood pressure equal to or higher than 130 / 85 mmHg; 2) fasting blood glucose equal to or higher than 100 mg / dL; 3) Large waist circumference, i.e. - For men, equal to or greater than 40 inches (approximately 101.6 cm); - For women, equal to or greater than 35 inches (approximately 88.9 cm); 4) Low HDL cholesterol, i.e. - For men, <40 mg / dL; - For women, <50 mg / dL; 5) Triglycerides equal to or greater than 150 mg / dL. Metabolic syndrome can be diagnosed by testing a subject's blood pressure, blood glucose levels, HDL cholesterol levels, LDL cholesterol levels, total cholesterol levels, and triglyceride levels.

[0064] As used herein, the term "agonist" refers to any chemical compound, naturally occurring or synthetic, that, upon interacting with (e.g., binding to) its target (e.g., MC4R), increases the signaling activity of MC4R above its basal level. Agonists can be superagonists (i.e., compounds capable of producing a maximal response that exceeds the endogenous agonism of the target receptor and therefore have an efficacy greater than 100%), full agonists (i.e., compounds that induce a maximal response following receptor occupation and activation), or partial agonists (i.e., compounds that can activate the receptor but are unable to induce the maximal response of the receptor system).

[0065] As used herein, "treating" refers to the achievement of the following outcomes: For example, a reduction in weight (e.g., measured by body mass index (BMI) and / or weight) compared to a control (e.g., pre-treatment weight or a predefined weight); For example, reducing waist circumference compared to a control (such as waist circumference, pre-treatment or pre-defined waist circumference); For example, reducing hunger levels compared to a control (such as pre-treatment hunger levels or pre-defined hunger levels); For example, increasing resting energy expenditure (REE) compared to a control (e.g., pre-treatment REE or a pre-defined REE); for example, decreasing food intake compared to a control level (e.g., pre-treatment or a pre-defined food intake); Ameliorating or improving the clinical symptoms or indications associated with a disorder described herein, such as obesity, type 2 diabetes, pre-diabetic conditions, hemoglobin A1C (Hb1Ac) blood levels greater than 6%, hyperinsulinemia, hyperlipidemia, insulin insensitivity or glucose intolerance; delaying, inhibiting or preventing the progression of obesity and / or obesity-related indications; or partially or completely delaying, inhibiting, or preventing the onset or progression of obesity or obesity-related indications; The method includes a step of achieving one or more of the following: Slowing, inhibiting, or preventing the progression of obesity includes, for example, delaying, inhibiting, or preventing a subject from progressing from normal weight to obesity. In embodiments, the control is a parameter value measured before treatment with an MC4R agonist described herein or a predefined value. The term "treating" further includes partially or completely reducing the risk for coronary artery disease, stroke, and type II diabetes associated with metabolic syndrome, as well as ameliorating or improving clinical symptoms or signs of metabolic syndrome (e.g., metabolic syndrome associated with any one or more of the above five indications). For example, the term "treating" includes slowing, inhibiting, or preventing the progression of parameters associated with metabolic syndrome (e.g., insulin resistance, glucose clearance, etc.), as well as parameters of cardiovascular disease (e.g., heart rate and blood pressure, etc.).

[0066] As used herein, "inhibition" or "inhibits" can encompass a reduction in a parameter, such as those parameters described herein. For example, inhibition of a parameter (e.g., activity) encompassed by this term can be at least 5%, 10%, 20%, 30%, 40%, or more. Thus, inhibition is not necessarily 100%.

[0067] "Prophylactic treatment" refers to treatment that prevents, inhibits, or reduces the occurrence of obesity before it occurs.

[0068] As used herein, the term "subject" refers to a mammal, such as, for example, a human. A subject can also refer to animals requiring veterinary treatment, such as companion animals (e.g., dogs, cats, and the like), livestock (e.g., cattle, sheep, pigs, horses, and the like), and laboratory animals (e.g., rats, mice, guinea pigs, and the like).

[0069] As used herein, the term "mutation" may refer to an altered nucleic acid sequence of a gene, or a fragment thereof, as compared to the wild-type sequence. For example, mutations may include point mutations, frameshift mutations, missense mutations, inversions, deletions, insertions, truncations, and chromosomal rearrangements. In embodiments, a mutation may result in a gene or a fragment thereof encoding a non-functional protein, a protein with reduced activity (or a partially functional protein), or a protein with altered activity. For example, a "loss of function" mutation refers to a mutation that results in a gene or a fragment thereof encoding a non-functional protein with substantially reduced activity compared to its wild-type counterpart (e.g., the activity of the non-functional protein is less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1% or less than its wild-type counterpart). For example, a "partial loss of function" mutation may refer to a mutation that results in a gene or a fragment thereof encoding a non-functional protein with substantially reduced activity compared to its wild-type counterpart (e.g., the activity of the non-functional protein is less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1% or less than its wild-type counterpart). A "loss of function" mutation refers to a mutation that results in a gene or fragment thereof encoding a partially functional protein that has reduced activity compared to its wild-type counterpart (e.g., a partially functional protein that has less than 50% to more than 10% of the activity of its wild-type counterpart).

[0070] As used herein, the term "unit dosage" refers to a physically discrete unit suitable as a unitary dosage for the subject to be treated, each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

[0071] As used herein, the term "dosage" refers to a quantity or amount of a therapeutic agent. In some embodiments, a dosage refers to an amount administered to a subject in a single administration (e.g., a single injection, a single infusion, or a single administration of one or more unit dosages). In embodiments, a dosage refers to an amount administered to a subject in multiple administrations (e.g., multiple injections, multiple infusions, or multiple administrations of one or more unit dosages). In other embodiments, dosage may refer to the total amount administered to a subject over a period of time (e.g., per day). In such instances, the dosage is typically referred to as a "daily dosage," i.e., the dosage converted to a daily amount.

[0072] As used herein, "hunger" or "hunger level" refers to a subject's perception of appetite, desire to consume food, or need for food. In an embodiment, a subject's hunger or hunger level can be quantified by using a scale that generates a hunger score. In an embodiment, on the hunger scale, the more frequently a subject feels unbearable hunger (e.g., frequently or all the time), the higher the score assigned, whereas the less frequently a subject feels unbearable hunger (e.g., occasionally or never), the lower the score assigned. See, for example, Sibilia, Psychologicol See "Topics," 19 (2010), Vol. 2, pp. 341-354. For example, a Likert hunger scale can be used to assign a score of 0 to 10 (0 = no hunger; 10 = severe hunger). In another embodiment, a Likert hunger scale can be used to assign a score of 1 to 4. On this Likert hunger scale, if a subject never experiences unbearable hunger, a score of 1 is assigned; if a subject only occasionally experiences unbearable hunger, a score of 2 is assigned; if a subject frequently experiences unbearable hunger, a score of 3 is assigned; and if a subject always experiences unbearable hunger, a score of 4 is assigned. See ibid.

[0073] hindrance In some embodiments, an MC4R agonist (e.g., an MC4R agonist described herein) is used in accordance with the methods and compositions described herein to treat a disorder (e.g., a metabolic disorder, e.g., obesity, hyperphagia, or metabolic syndrome). Prader-Willi syndrome (PWS)

[0074] Prader-Willi syndrome (PWS) is a rare genetic disorder with a prevalence in the United States of approximately 1 in 8,000 to 1 in 25,000 individuals. PWS is characterized by severe hyperphagia, which leads to a physiological urge to eat and ultimately to severe obesity and other complications. Obesity is one of the greatest health threats for individuals with PWS, and hyperphagia impairs individuals' ability to live independently and requires costly and constant supervision to prevent binge eating. Without supervision, these individuals are at high risk of choking, stomach rupture, or complications caused by morbid obesity, resulting in premature death. Currently, there are no approved treatments for obesity and hyperphagia associated with PWS.

[0075] Symptoms of PWS include infantile hypotonia with failure to thrive, rapid weight gain, and hyperphagia in childhood, as well as intellectual disability, developmental delay, short stature, and reproductive dysfunction. Diagnostic criteria for PWS are described, for example, in Holm et al., Pediatrics 91 (1993):398-402.

[0076] prognosis In embodiments, use of the methods described herein results in one or more of the following prognoses in a subject, for example, compared to a control: a decrease in weight (e.g., body weight), a decrease in hunger levels, no detectable decrease in energy expenditure (e.g., resting energy expenditure), an increase in energy expenditure (e.g., resting energy expenditure), a decrease in daily / weekly / monthly food intake, a decrease in the subject's waist circumference, no detectable increase in blood pressure, or a decrease in blood pressure.

[0077] In embodiments, the control is a measurement of the parameter in the subject prior to administration (treatment) of the MC4R agonist. In embodiments, the control is a predefined value, e.g., the value of the parameter in an average obese population (e.g., of a similar age and sex as the subject; or the value of the parameter measured in the subject at a previous time point (e.g., at a previous visit, by a doctor, medical facility, or laboratory, etc.)).

[0078] In embodiments, the subject's prognosis (e.g., a decrease, increase, no detectable decrease, or no detectable increase in a given parameter) is measured 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, or more after initiation of treatment with an MC4R agonist. In other embodiments, the subject's prognosis (e.g., a decrease, increase, no detectable decrease, or no detectable increase in a given parameter) is measured over a time period during the course of treatment (e.g., over 1-2 weeks, 2-4 weeks, 4-6 weeks, 6-8 weeks, 8-12 weeks, or 12-16 weeks or longer).

[0079] In embodiments, using the methods described herein, a subject experiences a weight loss (e.g., the subject's pre-treatment weight or a pre-defined weight, e.g., the average weight of a population of obese humans of the same age and sex who have not received the therapeutic intervention, or the subject's weight at a previous measurement (e.g., at a previous clinic visit)) compared to a control. In embodiments, weight loss is about 0.5-1 kg to 0.5-3 kg after 1 week of treatment, about 1 kg-6 kg after 2 weeks of treatment, about 2 kg-12 kg after 4 weeks of treatment, about 4 kg-24 kg after 8 weeks of treatment, or about 8 kg-48 kg after 16 weeks of treatment. In embodiments, weight loss occurs at a rate of about 0.5-2 kg / week (e.g., about 2 kg / week) over 1-2 weeks of treatment or longer, over 2-4 weeks of treatment or longer, over 4-8 weeks of treatment or longer, over 8-16 weeks of treatment, or over 16-32 weeks of treatment or longer.

[0080] Measurement of weight, eg, body weight, can be performed using standard methods in the art.

[0081] In embodiments, by using the methods described herein, the subject's hunger level (e.g., the subject's pre-treatment hunger level or a predefined hunger level, such as the average hunger level of a population of obese people of the same age and sex as the subject, or the subject's hunger level at a previous measurement (e.g., at a previous visit)) is reduced compared to a control. In embodiments, by using the methods described herein, the subject's feeling of hunger is eliminated.

[0082] In embodiments, hunger is measured on a scale such as the Likert Hunger Scale (ranging from 0 to 10) described herein. In embodiments, using the methods described herein, a subject's hunger score (e.g., the subject's pre-treatment hunger level or a pre-defined hunger level, e.g., the average hunger level of a population of obese individuals of the same age and gender as the subject, or the subject's hunger level at a previous measurement (e.g., at a previous clinic visit)) is reduced compared to a control. In embodiments, using the methods described herein, a subject's score on the Likert Hunger Scale (e.g., the subject's pre-treatment hunger level or a pre-defined hunger level, e.g., the average hunger level of a population of obese individuals of the same age and gender as the subject, or the subject's hunger level at a previous measurement (e.g., at a previous clinic visit)) is reduced by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points, for example, compared to a control. In an embodiment, the methods described herein result in a Likert hunger scale score of 0 after treatment.

[0083] In embodiments, the reduction in hunger levels is measured / observed after 1-2 weeks or longer of treatment, after 2-4 weeks or longer of treatment, after 4-8 weeks or longer of treatment, or after 8-16 weeks or longer of treatment.

[0084] REE is a measure of a subject's basal metabolic rate and can be quantified using methods described, for example, in Chen et al., The Journal of Clinical Endocrinology & Metabolism (J. Clin. Endocrinol. Metab) 100.4 (2015):1639-45. In embodiments, the subject may be placed in a whole-room indirect calorimeter (also called a metabolic chamber) at some point after treatment (e.g., 3, 4, 5, 6, or 7 days, or 1, 2, 3, 4, or more weeks) to quantitate REE. In embodiments, REE is measured over a 30-minute measurement period, and in some cases, the average REE is determined by averaging REE values ​​derived from several 30-minute periods. The average REE is calculated. In embodiments, REE can be quantified after a 10-12 hour fasting period, in a thermoneutral state (e.g., at about 25°C), while the subject is awake and free from psychological or physical stress. In embodiments, REE is measured in energy units per unit time (e.g., kcal / hour or kcal / day). In embodiments, REE is measured relative to the number of kg of lean body mass (e.g., REE / kg of lean mass) in a subject, for example, as described in the Examples.

[0085] In embodiments, the subject's energy expenditure (e.g., resting energy expenditure (REE)) is unchanged or not decreased using the methods described herein when measured hourly, daily (e.g., in a 24-hour period), weekly (e.g., in a 7-day period), or monthly (e.g., in a 30-day period), for example, 3, 4, 5, 6, 7 days, or 1, 2, 3, 4, or more weeks after treatment, compared to the control REE (e.g., the subject's pre-treatment REE or a pre-defined REE, e.g., the mean REE of an obese human population of the same age and sex as the subject and normalized for weight, or the subject's REE at a previous measurement (e.g., at a previous visit)).

[0086] In embodiments, the subject's energy expenditure (e.g., resting energy expenditure (REE) per kg of lean body mass) when measured using the methods described herein over an hourly, daily (e.g., 24-hour period), weekly (e.g., 7-day period), or monthly (e.g., 30-day period) period, for example, 3 days, 4 days, 5 days, 6 days, 7 days, or 1 week, 2 weeks, 3 weeks, 4 weeks, or more after treatment, shows no detectable change or no detectable decrease compared to the control REE (e.g., the subject's pre-treatment REE or a pre-defined REE, e.g., the mean REE of an obese human population of the same age and sex as the subject, or the subject's REE at a previous measurement (e.g., at a previous visit)).

[0087] In embodiments, the subject's energy expenditure (e.g., resting energy expenditure (REE)) is measured using the methods described herein over an hourly, daily (e.g., 24-hour period), weekly (e.g., 7-day period), or monthly (e.g., 30-day period) period, for example, 3 days, 4 days, 5 days, 6 days, 7 days, or 1 week, 2 weeks, 3 weeks, 4 weeks, or more after treatment, and shows an increase in energy expenditure compared to a control REE (e.g., the subject's pre-treatment REE or a pre-defined REE, e.g., the mean REE of an obese human population of the same age and sex as the subject and normalized for weight, or the subject's REE at a previous measurement (e.g., at a previous visit)).

[0088] In embodiments, the subject's REE increases by at least 20 kcal / day (e.g., at least 20 kcal / day, 30 kcal / day, 40 kcal / day, 50 kcal / day, 60 kcal / day, 70 kcal / day, 80 kcal / day, 90 kcal / day, 100 kcal / day, 110 kcal / day, 120 kcal / day, 130 kcal / day, 140 kcal / day, 150 kcal / day or more) when measured after 3, 4, 5, 6, 7 days, or 1, 2, 3, 4 or more weeks of treatment.

[0089] In embodiments, the subject's REE is increased by at least 2% (e.g., at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or more) compared to the subject's REE before treatment, e.g., when measured 3, 4, 5, 6, or 7 days, or 1, 2, 3, 4, or more weeks after treatment.

[0090] In embodiments, for example, in the case of an adult subject, the REE of the subject (e.g., adult subject) is increased by at least 1800 kcal / day (e.g., at least 1800 kcal / day, 1825 kcal / day, 1850 kcal / day, 1875 kcal / day, 1900 kcal / day, 1925 kcal / day, 1950 kcal / day, 1975 kcal / day, 2000 kcal / day, 2025 kcal / day, 2050 kcal / day, 2100 kcal / day, 2150 kcal / day, 2200 kcal / day, 2250 kcal / day, 2300 kcal / day, 2400 kcal / day, or more) after treatment with an MC4R agonist (e.g., after 3, 4, 5, 6, 7 days, or 1, 2, 3, 4, or more weeks of treatment). In embodiments, for example, in the case of a pediatric patient, the subject's (e.g., pediatric subject's) REE is increased by at least 200 kcal / day (e.g., at least 200 kcal / day, 225 kcal / day, 250 kcal / day, 275 kcal / day, 300 kcal / day, 325 kcal / day, 350 kcal / day, 375 kcal / day, 400 kcal / day, 450 kcal / day, 500 kcal / day, or more) after treatment with an MC4R agonist (e.g., after 3, 4, 5, 6, 7 days, or 1, 2, 3, 4, or more weeks of treatment).

[0091] In embodiments, the subject's food intake is reduced using the methods described herein, e.g., when food intake is measured as daily food intake, or food intake over a 24-hour or weekly period, compared to a control (e.g., the subject's food intake before treatment, or a pre-defined food intake level, e.g., the food intake of an average obese population, or the subject's food intake at a previous measurement (e.g., at a previous visit)). In embodiments, e.g., for an adult subject, a reduction in daily food intake, or food intake over a 24 hour period or a week or 30 days or longer period, of at least 100 kcal (e.g., at least 100 kcal, 125 kcal, 150 kcal, 175 kcal, 200 kcal, 225 kcal, 250 kcal, 275 kcal, 300 kcal, 325 kcal, 350 kcal, 375 kcal, 400 kcal, 425 kcal, 450 kcal, 475 kcal, 500 kcal, 525 kcal, 550 kcal, 575 kcal, 600 kcal, 1000 kcal or more) is observed. In embodiments, the average food intake in a pediatric subject about one year old can be reduced from a baseline of about 100 kcal / kg / day or more to about 90 kcal / kg / day, 80 kcal / kg / day, 70 kcal / kg / day, 60 kcal / kg / day, 50 kcal / kg / day, 40 kcal / kg / day, 30 kcal / kg / day, 20 kcal / kg / day, or 10 kcal / kg / day, or less, after treatment with an MC4R agonist. In embodiments, the average food intake in a pediatric subject in late adolescence can be reduced from a baseline of about 40 kcal / kg / day or more to about 35 kcal / kg / day, 30 kcal / kg / day, 20 kcal / kg / day, or 10 kcal / kg / day, or less, after treatment with an MC4R agonist.

[0092] Food intake can be quantified by standard methods, for example, as described in Rutishauser, Public Health Nutrition 8.7A (2005):1100-07.

[0093] In embodiments, the subject's waist circumference is reduced when measured 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks or longer after initiation of treatment using the methods described herein, compared to a control (e.g., the subject's waist circumference before treatment, or the subject's waist circumference at a previous measurement (e.g., at a previous visit).

[0094] In embodiments, the waist circumference of a subject (e.g., an adult subject) is reduced by at least 2 cm (e.g., at least 2 cm, 3 cm, 4 cm, 5 cm, 6 cm, 7 cm, 8 cm, 9 cm, 10 cm or more) when measured 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks or longer after initiation of treatment compared to a control (e.g., the subject's pre-treatment waist circumference or a pre-defined waist circumference, e.g., the waist circumference of a population of obese people of the same age and sex, or the subject's waist circumference at a previous measurement (e.g., at a previous clinic visit)).

[0095] In some embodiments, waist circumference is measured using standard methods. In some embodiments, waist circumference is the maximum circumference around the subject's midsection (e.g., around the subject's abdomen). In other embodiments, waist circumference is measured around the natural waist (e.g., from the lowest rib to the top of the hipbone), the navel, or the narrowest point around the midsection.

[0096] In embodiments, the subject's blood pressure (e.g., diastolic and / or systolic pressure) is not detectably elevated using the methods described herein when the blood pressure is measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more weeks after initiation of treatment compared to a control blood pressure (e.g., the subject's pre-treatment blood pressure or a pre-defined blood pressure, e.g., the average blood pressure of a population of obese people of the same age and sex, or the subject's blood pressure at a previous measurement (e.g., at a previous clinic visit)).

[0097] In embodiments, the subject's blood pressure (e.g., diastolic and / or systolic pressure) is reduced using the methods described herein when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more weeks after initiation of treatment compared to a control blood pressure (e.g., the subject's pre-treatment blood pressure or a pre-defined blood pressure, e.g., the average blood pressure of a population of obese people of the same age and sex, or the subject's blood pressure at a previous measurement (e.g., at a previous clinic visit)).

[0098] In embodiments, blood pressure (e.g., systolic pressure) is reduced by at least 1 mmHg, 2 mmHg, or 3 mmHg (e.g., at least 3 mmHg, 3.5 mmHg, 4 mmHg, 4.5 mmHg, 5 mmHg, 5.5 mmHg, 6 mmHg, 6.5 mmHg, 7 mmHg, or more) compared to the subject's blood pressure before treatment when measured 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, or more after initiation of treatment.

[0099] In embodiments, blood pressure (e.g., diastolic pressure) is reduced by at least 4 mmHg (e.g., at least 4 mmHg, 7 mmHg, 7.5 mmHg, 8 mmHg, 8.5 mmHg, 9 mmHg, 9.5 mmHg, 10 mmHg or more) compared to the subject's blood pressure before treatment when measured 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks or more after initiation of treatment.

[0100] In embodiments, the methods described herein do not have adverse effects on heart rate or blood pressure.

[0101] subject According to any of the methods described herein, in certain embodiments, the subject is obese prior to administration (e.g., an agonist described herein) (e.g., at the time the agonist is prescribed or initially administered). In embodiments, the subject is a severely obese pediatric patient or adult patient prior to administration (e.g., at the time the agonist is prescribed or initially administered) of an agonist described herein. In embodiments, the subject is obese prior to administration (e.g., at the time the agonist is prescribed or initially administered) of an agonist described herein (e.g., an agonist described herein).

[0102] In embodiments, the body mass index (BMI) of the subject (e.g., an adult subject) prior to administration of the agonist (e.g., at the time the agonist is prescribed or first administered) is 25 kg / m 2 Over 30kgm 2 Over (e.g., 25 kg / m 2 More than 26kg / m 2 More than 27kg / m 2 More than 28kg / m 2 More than 29kg / m 2 More than 30kg / m 2 More than 31kg / m 2 More than 32kg / m 2 More than 33kg / m 2 More than 34kg / m2 More than 35kg / m 2 More than 36kg / m 2 More than 37kg / m 2 More than 38kg / m 2 More than 39kg / m 2 More than 40kg / m 2 More than 41kg / m 2 More than 42kg / m 2 More than 43kg / m 2 More than 44kg / m 2 More than 45kg / m 2 More than 46kg / m 2 More than 47kg / m 2 More than 48kg / m 2 More than 49kg / m 2 More than 50kg / m 2 (greater than or equal to the value).

[0103] In an embodiment, prior to administration of the agonist (e.g., at the time the agonist is prescribed or at the time of the first administration), the subject (e.g., a pediatric subject) has a body mass index (BMI) greater than the 85th to 95th percentile.

[0104] In embodiments, the subject's body weight before administration of the agonist (e.g., when the agonist is prescribed or initially administered) is at least about 5 kg, e.g., at least about 5 kg, 10 kg, 20 kg, 30 kg, 40 kg, 50 kg, 60 kg, 70 kg, 80 kg, 90 kg, 100 kg, 110 kg, 120 kg, 130 kg, 140 kg, 145 kg, 150 kg, 155 kg, 160 kg, 165 kg, 170 kg, 175 kg, 180 kg, 185 kg, 190 kg, 200 kg, 205 kg, 210 kg, 215 kg, 220 kg or more, or greater. In embodiments, the subject's body weight before administration of the agonist (e.g., when the agonist is prescribed or initially administered) is at least 20 kg, at least 60 kg, or at least 100 kg.

[0105] In embodiments, the subject is an adult, e.g., 18 years of age or older (e.g., 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, or older).

[0106] In embodiments, the subject is a pediatric subject, e.g., 18 years of age or younger (e.g., 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 year old, or younger).

[0107] In yet another aspect, the present invention provides a method for eliciting an agonist effect from a melanocortin receptor in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof.

[0108] In another aspect, the present invention provides a method for eliciting an agonist effect from a melanocortin 4 receptor in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula (I) or Formula (II) as defined above, or a pharmaceutically acceptable salt thereof, wherein the compound is a selective melanocortin 4 receptor agonist.

[0109] In a further aspect, the present invention provides a method for eliciting an agonist or antagonist effect from a melanocortin 4 receptor in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof, wherein the compound is a selective melanocortin 4 receptor agonist.

[0110] In yet another aspect, the present invention provides a method for eliciting an agonist effect from a melanocortin 4 receptor in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula (I) or Formula (II) as defined above, or a pharmaceutically acceptable salt thereof, wherein the compound is a selective melanocortin 4 receptor agonist.

[0111] In another aspect, the present invention provides a method for treating acute or chronic inflammatory diseases or medical conditions, such as systemic inflammation, inflammatory bowel disease, encephalitis, sepsis and septic shock, by administering an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof, to elicit an agonist effect from a melanocortin receptor.

[0112] In another aspect, the present invention provides a method for treating diseases or medical conditions with an autoimmune component, such as rheumatoid arthritis, gouty arthritis and multiple sclerosis, by administering an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof, to elicit an agonist effect from the melanocortin receptor.

[0113] In another aspect, the present invention provides a method for treating metabolic diseases or medical conditions associated with weight gain, such as obesity, eating disorders, and Prader-Willi syndrome, by administering an effective amount of a compound of Formula (I) or Formula (II) as defined above, or a pharmaceutically acceptable salt thereof, to elicit an agonist effect at the melanocortin receptor. In a further aspect of the above method, the disease or condition being treated is obesity. In yet a further aspect of the above method, the disease or condition being treated is an eating disorder characterized by hyperphagia and / or obesity.

[0114] In another aspect, the present invention provides a method for reducing food intake, reducing body weight, or a combination thereof, by administering an effective amount of a compound of formula (I) or formula (II), as defined above, or a pharmaceutically acceptable salt thereof, to elicit an agonist effect at melanocortin receptors. In one embodiment, the present invention provides a method for reducing food intake, reducing body weight, or a combination thereof, by administering an effective amount of a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, to elicit an agonist effect at melanocortin receptors.

[0115] In another embodiment, the present invention provides a method for reducing food intake, reducing body weight, or a combination thereof, by administering an effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, to elicit an agonist effect from a melanocortin receptor.

[0116] In another embodiment, the present invention provides a method for reducing food intake, reducing body weight, or a combination thereof, by administering an effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, to elicit an agonist effect at the melanocortin receptor. In another embodiment, the present invention provides a method for reducing food intake, reducing body weight, or a combination thereof, by administering an effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, to elicit an agonist effect at the melanocortin receptor.

[0117] In another aspect, the present invention provides a method for reducing appetite without loss of body weight by administering an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof. In another aspect, the present invention provides a method for reducing food consumption and simultaneously losing body weight by administering an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof.

[0118] In another aspect, the present invention provides a method for treating reproductive or sexual medical conditions (e.g., endometriosis, uterine bleeding, sexual dysfunction, erectile dysfunction, and diminished sexual response in women) by administering an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof, to elicit an agonist effect at the melanocortin receptor.

[0119] In another aspect, the present invention provides a method for treating a disease or medical condition resulting from a treatment or insult to an organism (e.g., organ transplant rejection, ischemic injury, reperfusion injury, wound and spinal cord injury, and weight loss due to chemotherapy, radiation therapy, temporary or permanent stiffening, or dialysis resulting from a medical procedure selected from the group consisting of chemotherapy, radiation therapy, temporary or permanent stiffening, and dialysis), by administering an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof, to elicit an agonist effect from a melanocortin receptor.

[0120] In another aspect, the present invention provides a method for treating cardiovascular diseases or medical conditions (e.g., hemorrhagic shock, cardiogenic shock, hypovolemic shock, cardiovascular disorders, and cardiac cachexia) by administering an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof, to elicit an agonist effect from a melanocortin receptor.

[0121] In another aspect, the present invention provides a method for treating pulmonary diseases or medical conditions (e.g., acute respiratory distress syndrome, pulmonary fibrosis, chronic obstructive pulmonary disease, and asthma) by administering an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof, to elicit an agonist effect at a melanocortin receptor.

[0122] In another aspect, the present invention provides a method for enhancing immune tolerance or treating allergy by administering an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof, to elicit an agonist effect from the melanocortin receptor.

[0123] In another aspect, the present invention provides a method for treating dermatological diseases or medical conditions (e.g., psoriasis, erythropoietic protoporphyria, loss of skin pigmentation, acne, and keloid formation) by administering an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof.

[0124] In another aspect, the present invention provides a method for treating behavioral, central nervous system, or neurological diseases or medical conditions (e.g., agony, depression, memory dysfunction, and neuropathic pain) by administering an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof, to elicit an agonist effect from a melanocortin receptor.

[0125] In another aspect, the present invention provides a method for treating kidney diseases or medical conditions (e.g., renal cachexia and natriuresis) by administering an effective amount of a compound of formula (I) or formula (II), as defined above, or a pharmaceutically acceptable salt thereof, to elicit an agonist effect from a melanocortin receptor.

[0126] In another aspect, the present invention provides a method for modulating normal or homeostatic activities (e.g., ovarian weight, placental development, prolactin secretion, FSH secretion, intrauterine fetal growth, parturition, spermatogenesis, thyroxine release, aldosterone synthesis and release, gonadal development, body temperature, blood pressure, heart rate, vascular tone, cerebral blood flow, blood glucose levels, sebum secretion, pheromone secretion, motivation, learning and behavior, pain sensation, neuroprotection and neuronal growth) by administering an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof, to elicit an agonist effect from the melanocortin receptor.

[0127] In another aspect, the present invention provides a method for regulating normal or homeostatic activities (e.g., bone metabolism, bone formation, and bone development) by administering an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof, to elicit an agonist effect from a melanocortin receptor.

[0128] In another aspect, the present invention provides a method for inhibiting alcohol consumption, reducing alcohol consumption, treating alcoholism, or treating excessive alcohol drinking by administering an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof, to elicit an agonist effect at the melanocortin receptor. In a further aspect of the above method, the compound is a selective melanocortin 4 receptor agonist.

[0129] In further embodiments, the present invention relates to the treatment of acute and chronic inflammatory diseases, such as systemic inflammation, inflammatory bowel disease, encephalitis, sepsis and septic shock; diseases with an autoimmune component, such as rheumatoid arthritis, gouty arthritis and multiple sclerosis; metabolic diseases and medical disorders associated with weight gain, such as obesity, eating disorders and Prader-Willi syndrome; metabolic diseases and medical disorders associated with weight loss, such as anorexia, hyperphagia, AIDS wasting, cachexia, cancer cachexia and wasting in frail elderly people; diabetes and diabetologically related diseases and complications of diabetes, such as retinal disorders; neoplastic growths, such as skin cancer and prostate cancer; reproductive or sexual medical conditions, such as endometriosis and uterine bleeding in women, sexual dysfunction, erectile dysfunction and diminished sexual response in women; diseases or medical conditions resulting from treatment or insult to the organism, such as organ transplant rejection, ischemic injury, reperfusion injury, spinal cord injury and wounds, and chemotherapy, radiotherapy, and treatment of dermatological diseases and conditions such as psoriasis, loss of skin pigmentation, acne, keloid formation, and skin cancer. The present invention provides a method for the treatment of renal conditions or diseases, such as renal cachexia and natriuresis.

[0130] In a further aspect, the present invention provides the use of a therapeutically effective amount of a melanocortin 4 receptor agonist compound according to formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful for regulating normal or homeostatic activities (e.g., ovarian weight, placental development, prolactin secretion, FSH secretion, intrauterine fetal growth, parturition, spermatogenesis, gonadal development, thyroxine release, aldosterone synthesis and release, body temperature, blood pressure, heart rate, vascular tone, cerebral blood flow, blood glucose levels, sebum secretion, pheromone secretion, motivation, learning and behavior, pain sensation, neuroprotection, nerve growth, bone metabolism, bone metabolism, bone formation and bone development).

[0131] Of course, therapeutic interventions that address both normal physiological and pathophysiological processes that utilize melanocortin receptors are also contemplated.

[0132] Compounds of formula (I) or (II) are ligands for at least one of the melanocortin receptors (MC1-R, MC2-R, MC3-R, MC4-R and MC5-R) and were tested for their ability to act as ligands for selected melanocortin receptors in the in vitro assays described below.

[0133] Also provided herein in some aspects are methods for assessing a subject's potential responsiveness to, for example, an MC4R agonist described herein, in some embodiments, the method includes obtaining information about the subject's genotype.

[0134] In embodiments, identifying a subject with a defect, e.g., a genetic defect such as a mutation, indicates that the subject is likely to respond to an MC4R agonist (e.g., an MC4R agonist described herein) (e.g., by improvement in one or more symptoms). In embodiments, improvement in symptoms may encompass a prognosis described herein. For example, improvement in symptoms may encompass, e.g., a loss of weight (e.g., body weight), a decrease in hunger levels, no detectable decrease in energy expenditure (e.g., resting energy expenditure), an increase in energy expenditure (e.g., resting energy expenditure), a decrease in daily / weekly / monthly food intake, or a decrease in the subject's waist circumference, e.g., compared to a control.

[0135] In embodiments, the methods described herein further include providing a report identifying the presence or absence of the genetic defect (and in some cases an identifier for the subject). In embodiments, the report provides recommendations regarding possible treatment options, the likely effects of the treatment options, and / or recommendations / directions for administering the treatment options (e.g., MC4R agonists described herein).

[0136] MC4R agonists The present invention provides MC4R agonists according to Formula I. [ka] During the ceremony, Aaa, Bbb = Cys, hCys, Pen capable of establishing disulfide bridges; or It is selected from Glu, Asp, Lys, Om, Dpr, Dbu, which are capable of establishing a lactam bridge. Xxx=Asn, Gln, Ser, Thr Yyy = Lys, Arg, D-Lys, D-Arg A1=H, Ac A2=OH, NH2 Ac is acyl (eg, acetyl).

[0137] In embodiments, the MC4R agonist has a structure according to Formula II: [ka] wherein Xxx is Asn, Gln, Ser, or Thr; A1 is H or Ac; A2 is OH or NH2, and Yyy is Lys, Arg, D-Lys, or D-Arg.

[0138] In embodiments, the MC4R agonist is selected from one or more of the following compounds (or pharmaceutically acceptable salts thereof): 001554C: Ac-Arg-(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 1) 001555C: Ac-Arg-(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 2), 001556C: Ac-Arg-(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 3), 001574C: Ac-Arg-(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 4), 001576C: Ac-Arg-(Glu-Gln-D-Phe-Arg-Trp-Apr)-NH2 (SEQ ID NO: 5), Ac-Arg-(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 6), H-Arg-(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 7), H-Arg-(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 8), Ac-D-Arg-(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 9), HD-Arg-(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 10), Ac-D-Arg-(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 11), HD-Arg-(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 12), Ac-Lys-(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 13), Ac-Lys-(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 14), H-Lys-(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 15), H-Lys-(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 16), Ac-D-Lys-(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 17), HD-Lys-(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 18), Ac-D-Lys-(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 19), HD-Lys-(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 20), Ac-Arg-(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 21), H-Arg-(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 22), H-Arg-(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 23), Ac-D-Arg-(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 24), HD-Arg-(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 25), Ac-D-Arg-(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 26), HD-Arg-(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 27), Ac-Lys-(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 28), Ac-Lys-(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 29), H-Lys-(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 30), H-Lys-(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 31), Ac-D-Lys-(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 32), HD-Lys-(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 33), Ac-D-Lys-(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 34), HD-Lys-(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 35), Ac-Arg-(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 36), H-Arg-(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 37), H-Arg-(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 38), Ac-D-Arg-(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 39), HD-Arg-(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 40), Ac-D-Arg-(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 41), HD-Arg-(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 42), Ac-Lys-(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 43), Ac-Lys-(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 44), H-Lys-(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 45), H-Lys-(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 46), Ac-D-Lys-(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 47), HD-Lys-(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 48), Ac-D-Lys-(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 49), HD-Lys-(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 50), Ac-Arg-(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 51), H-Arg-(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 52), H-Arg-(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 53), Ac-D-Arg-(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 54), HD-Arg-(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 55), Ac-D-Arg-(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 56), HD-Arg-(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 57), Ac-Lys-(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 58), Ac-Lys-(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 59), H-Lys-(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 60), H-Lys-(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 61), Ac-D-Lys-(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 62), HD-Lys-(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 63), Ac-D-Lys-(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 64) or HD-Lys-(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 65) The EC-50 and selectivity ratios of exemplary compounds of the present invention are as follows: 001554C: Ac-Arg-(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 1), 001555C: Ac-Arg-(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 2), 001556C: Ac-Arg-(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 3), 001574C: Ac-Arg-(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 4), 001576C: Ac-Arg-(Glu-Gln-D-Phe-Arg-Trp-Apr)-NH2 (SEQ ID NO: 5)

[0139] Administering a compound or a pharmaceutically acceptable salt thereof useful in practicing the methods described herein, or a composition comprising a compound or pharmaceutical salt of a compound of the invention, can be continuous, hourly, four times a day, three times a day, twice a day, once a day, every other day, twice a week, once a week, every other week, once a month, every other month, or over a longer period of time, or any other intermittent dosing regimen.

[0140] Examples of administration of the compounds, or compositions comprising the compounds, or pharmaceutical salts of the compounds of the invention include peripheral administration, including oral, subcutaneous, intraperitoneal, intramuscular, intravenous, rectal, transdermal, or intranasal administration.

[0141] As used herein, peripheral administration may encompass all forms of administering a compound or composition comprising a compound of the present invention, other than intracranial administration. Examples of peripheral administration include, but are not limited to, oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, or subcutaneous injection, sustained-release, sustained-release implants, depots, and the like), nasal, vaginal, rectal, sublingual, or topical routes of administration (including transdermal patch applications and the like).

[0142] In the nomenclature used to define peptides as typically used in the art, the N-terminal amino group appears on the left and the C-terminal carboxyl group appears on the right. Where an amino acid has D- and L-isomeric forms, the L-amino acid is represented unless expressly indicated otherwise.

[0143] The compounds of the present invention useful for carrying out the methods described herein have one or more chiral centers and may exist as such in several stereoisomeric forms. All stereoisomers and mixtures thereof are within the scope of the present invention. Racemic compounds can be separated using preparative HPLC and a column containing a chiral stationary phase, or individual enantiomers can be produced by resolution using methods known to those skilled in the art. In addition, chiral intermediate compounds can be resolved and used to prepare the chiral compounds of the present invention.

[0144] The compounds described herein may exist in one or more tautomeric forms. All tautomers and mixtures thereof are within the scope of the present invention. For example, if a claim is made to 2-hydroxypyridinyl, its tautomeric form, α-pyridinyl, is also claimed.

[0145] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs, and all publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. [Table 1]

[0146] Unless otherwise stated, in this disclosure, all abbreviations for amino acids other than the N-terminal amino acid (e.g., Ala) represent the structure -NH-C(R)(R')-CO-, where R and R' are each independently hydrogen or the side chain of an amino acid (e.g., R=CH3 and R'=H in alanine (Ala)), or R and R' can be joined to form a ring system.

[0147] Pharmaceutical Composition / Administration According to any of the methods or compositions described herein, in embodiments, provided herein is a unit dosage of an MC4R agonist described herein. In embodiments, the unit dosage includes 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, or 2 mg of the agonist. In embodiments, the unit dosage is suitable for injection (e.g., subcutaneous injection). In embodiments, the unit dosage is disposed within a delivery device suitable for injection (e.g., subcutaneous injection). In embodiments, the unit dosage is disposed within a syringe or pen-type injector suitable for injection (e.g., subcutaneous injection). Exemplary pen-type injectors are described, for example, in U.S. Pat. No. 8,512,297 B2, U.S. Pat. No. 5,688,251 A, U.S. Pat. No. 5,820,602 A, U.S. Pat. No. 2014 / 0163526 A1, and U.S. Pat. No. 5,226,895 A, which are incorporated herein by reference.

[0148] Also provided herein, in embodiments, are pharmaceutical compositions comprising the MC4R agonists described herein. In embodiments, the pharmaceutical compositions include a therapeutically effective amount of the MC4R agonists described herein. A therapeutically effective amount of an agonist can vary depending on factors such as the individual's disease state, age, sex, and weight, as well as the ability of the agonist to elicit a desired response in the individual, such as at least one disorder parameter (e.g., an obesity or bulimia parameter) or amelioration of at least one symptom of a disorder, such as obesity, bulimia, or Prader-Willi syndrome (PWS). Also, in embodiments, a therapeutically effective amount is an amount in which any toxic or detrimental effects of the composition are outweighed by the therapeutically beneficial effects.

[0149] In certain embodiments, the agonist may be formulated with a carrier that will protect against rapid release (e.g., a controlled-release formulation, such as implants and microencapsulated delivery systems). Biodegradable, biocompatible polymers (e.g., ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid) may also be used. Many methods for preparing such formulations are patented or generally known. See, for example, "Sustained and Controlled Release Drug Delivery Systems," by J.R. Robinson (Marcel Dekker, Inc., New York, 1978).

[0150] In other embodiments, the agonist may be prepared using the methods described in WO 2014 / 144842, which is incorporated herein by reference. In embodiments, the agonist is prepared in a formulation including an anionic excipient, e.g., a PEG carboxylic acid, a fatty acid having 10 or more carbon atoms, and / or an anionic phospholipid. In embodiments, the anionic phospholipid is described in WO 2014 / 144842 (e.g., pages 7-9). In some embodiments, the anionic phospholipid is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), optionally conjugated to polyethylene glycol (PEG). Its structure is as follows: [ka] The value of "n" varies depending on molecular weight. In embodiments, fatty acids are described in WO 2014 / 144842 (e.g., page 9). In embodiments, PEG carboxylic acids are described in WO 2014 / 144842 (e.g., pages 9-11). In embodiments, the molar ratio of agonist to anionic excipient ranges from about 1:1 to about 1:10.

[0151] In embodiments, the agonist forms an ionically bonded complex with other components of the formulation, e.g., to provide a desirable pharmacokinetic profile for the agonist (e.g., extend the duration of drug action and / or minimize adverse effects). In embodiments, the formulation is a sustained-release formulation. In embodiments, fluctuations in the concentration of the agonist are reduced following administration of the formulation.

[0152] The MC4R agonists described herein can be administered to a subject (e.g., a human subject) in a variety of ways. In embodiments, the route of administration is any one of intravenous injection, intravenous infusion, subcutaneous injection, or intramuscular injection. In embodiments, the route of administration is subcutaneous injection.

[0153] In embodiments, for example, pharmaceutical compositions containing the MC4R agonists described herein may be administered using a medical device. For example, compositions containing the agonists may be administered with a needleless hypodermic injection device (e.g., devices disclosed in U.S. Patent Nos. 5,399,163, 5,383,851, 5,312,335, 5,064,413, 4,941,880, 4,790,824, or 4,596,556). Examples of implants and modules include an implantable microinfusion pump for dispensing drugs at a controlled rate, such as that disclosed in U.S. Patent No. 4,487,603; a therapeutic device for administering drugs through the skin, such as that disclosed in U.S. Patent No. 4,486,194; a drug infusion pump for delivering drugs at precise infusion rates, such as that disclosed in U.S. Patent No. 4,447,233; a variable flow rate implantable infusion device for continuous drug delivery, such as that disclosed in U.S. Patent No. 4,447,224; an osmotic drug delivery system with multiple chamber compartments, such as that disclosed in U.S. Patent No. 4,439,196; and an osmotic drug delivery system, such as that disclosed in U.S. Patent No. 4,475,196. Other such implants, delivery systems, and modules may also be used.

[0154] In embodiments, continuous administration may be indicated, for example, via a subcutaneous pump. In embodiments, the agonist is administered via a syringe (e.g., a pre-filled syringe), an implantable device, a needleless hypodermic injection device, an infusion pump (e.g., an implantable infusion pump), or an osmotic delivery system.

[0155] In embodiments, the agonist is administered, e.g., subcutaneously, in a unit dosage of, e.g., 0.1 to 10 mg (including 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, or 10 mg of agonist).

[0156] In embodiments, the agonist is administered, for example, as a subcutaneous bolus, at a dose of 0.1 to 10 mg (e.g., 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, or 10 mg of agonist).

[0157] In embodiments, the agonist is administered continuously, for example via a pump, such as a subcutaneous pump.

[0158] In embodiments, the agonist (e.g., a unit dosage of the agonist) is disposed within a delivery device, such as a syringe (e.g., a pre-filled syringe), an implantable device, a needleless hypodermic injection device, an infusion pump (e.g., an implantable infusion pump), or an osmotic delivery system.

[0159] In an embodiment, a daily dosage of the agonist is administered to a subject, for example, subcutaneously. In an embodiment, the daily dosage of the agonist administered subcutaneously is, for example, about 0.1 mg to about 10 mg (e.g., 0.1 to 0.2 mg, 0.2 to 0.4 mg, 0.4 to 0.6 mg, 0.6 to 0.8 mg, 0.8 to 1 mg, 1 to 1.2 mg, 1.2 to 1.5 mg, 1.5 to 2 mg, 2 to 2.5 mg, 2.5 to 3 mg, 3 to 3.5 mg, 3.5 to 4 mg, 4 to 4.5 mg, 4.5 to 5 mg, 5 to 5.5 mg, 5.5 to 6 mg, 6 to 6.5 mg, 6.5 to 7 mg, 7 to 7.5 mg, 7.5 to 8 mg, 8 to 8.5 mg, 8.5 to 9 mg, 9 to 9.5 mg, or 9.5 to 10 mg).

[0160] In embodiments, the administration frequency of the agonist is at least 3 weeks (e.g., at least 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 53 weeks, 54 weeks, 55 weeks, 56 weeks, 57 weeks, 58 weeks, 59 weeks, 60 weeks, 61 weeks, 62 weeks, 63 weeks, 64 weeks, 65 weeks, 66 weeks, 67 weeks, 68 weeks, 69 weeks, 70 weeks, 71 weeks, 72 weeks, 73 weeks, 74 weeks, 75 weeks, 76 weeks, 77 weeks, 78 weeks, 79 weeks, 80 weeks, 81 weeks, 82 weeks, 83 weeks, 84 weeks, 85 weeks, 86 weeks, 87 weeks, 88 weeks, 89 weeks, 90 weeks, 91 weeks, 92 weeks, 93 weeks, 94 weeks, 95 weeks, 96 weeks, 97 weeks, 98 weeks, 99 weeks, 100 weeks, 1 For example, the agonist is administered once or multiple times over a period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months or more, or over a period of at least 1, 2, 3, 4, or more years. In an embodiment, the agonist is administered multiple times, and the time interval between any two administrations is at least 6 hours (e.g., 6 hours, 12 hours, 24 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 1 week, 2 weeks, 3 weeks, 4 weeks, or more). In an embodiment, the interval between two administrations is one day.

[0161] kit The MC4R agonists described herein can be provided in a kit. The kit includes an MC4R agonist described herein, and optionally a container, a pharmaceutically acceptable carrier, and / or informational material. The informational material can be instructional, educational, marketing, or other material relating to the methods described herein and / or the use of the agonists in the methods described herein.

[0162] The informational material of the kit is not limited to its form. In one embodiment, the informational material can include information about the production of the agonist, the agonist's physical properties, concentration, expiration date, batch or production site information, etc. In one embodiment, the informational material relates to, for example, routes of administration described herein and / or methods of administering the agonist at the doses and / or dosing schedules described herein.

[0163] In one embodiment, the informational material may include instructions for administering an agonist described herein in a suitable manner (e.g., in a suitable dose, dosage form, or mode of administration, such as a dose, dosage form, or mode of administration described herein) for practicing the methods described herein. In another embodiment, the informational material may include instructions for administering the agonist to a suitable subject, e.g., a human, e.g., an obese person (such as a severely obese person).

[0164] The informational material of the kit is not limited in its form. In many instances, the informational material, e.g., instructions, may be provided in printed form, e.g., (printed text), drawings, and / or photographs (e.g., labels or printed sheets). However, the informational material can also be provided in other formats (e.g., Braille, computer-readable material, video recording, or audio recording). In another embodiment, the informational material of the kit is contact information (e.g., a physical address, email address, website, or phone number) that will enable a user of the kit to obtain sufficient information about the agonists described herein and / or how to use the agonists in the methods described herein. It is also possible to provide the informational material in any combination of formats.

[0165] In addition to the agonist, the compositions of the kits may include other ingredients (e.g., surfactants, lyoprotectants or stabilizers, antioxidants, antimicrobial agents, bulking agents, chelating agents, inert gases, tonics, and / or viscosity agents, solvents or buffers, stabilizers, preservatives, pharmaceutically acceptable carriers, and / or second agents for treating a condition or disorder described herein. Alternatively, the other ingredients may be included in the kits but in a different composition or container than the agonist described herein.

[0166] In some embodiments, the kit components are stored in vials sealed with rubber or silicone closures (e.g., polybutadiene or polyisoprene closures). In some embodiments, the kit components are stored under inert conditions (e.g., nitrogen or another inert gas (e.g., argon)). In some embodiments, the kit components can be stored anhydrous, for example, using a desiccant. In some embodiments, the kit components are stored in light-proof containers, such as amber vials.

[0167] The agonists described herein can be provided in any form, for example, liquid, frozen, dried, or lyophilized. Compositions containing the agonists described herein are preferably substantially pure and / or sterile. When the agonists described herein are provided in a liquid solution, the liquid solution is preferably an aqueous solution (preferably a sterile aqueous solution). In one embodiment, the agonist is provided with a diluent or instructions for dilution. The diluent may include, for example, saline or saline solution (e.g., sodium chloride solution, pH 6-9), lactated Ringer's injection, 5% dextrose in water (D5W), or PLASMA-LYTE A Injection® (pH 7.4) (Baxter, Deerfield, Illinois).

[0168] The kit may include one or more containers for compositions containing an agonist described herein. In some embodiments, the kit includes separate containers, dividers, or compartments for the composition and informational material. For example, the composition can be contained in a bottle, vial, IV admixture bag, IV set, piggyback set, or syringe (e.g., a pre-filled syringe), and the informational material can be contained in a plastic sleeve or packet. In other embodiments, the separate elements of the kit are contained within a single, undivided container. For example, the composition can be contained in a bottle, vial, or syringe to which the informational material, in the form of a label, is attached. In embodiments, the composition is contained within an injector device (e.g., a pen-type injector). The containers of the kit can be airtight and waterproof (e.g., impervious to changes in moisture or evaporation) and / or light-resistant. [Example]

[0169] The present invention is described in further detail by reference to the following experimental examples. These examples are provided for illustrative purposes only and, unless otherwise specified, are not intended to be limiting. Therefore, the present invention should not be construed as being limited solely to the following examples, but rather as embracing any and all variations thereof. These variations will become apparent from the teachings provided herein.

[0170] Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the compounds of the present invention and practice the claimed methods. The following examples specifically point out various aspects of the present invention, but are not to be construed as limiting in any way the remainder of the disclosure.

[0171] Example 1: Synthesis of Polypeptides of Formulas (I and II) Polypeptides of formulas (I and II) were prepared by conventional solid-phase peptide synthesis. First, an amino acid derivative at the C-terminal end of the polypeptide is attached to a suitable solid support resin known to be suitable for peptide synthesis, followed by stepwise elongation of the peptide chain. To synthesize peptides with a C-terminal amide functional group, Rink amide MBHA resin was used as the solid support. To synthesize peptides with a C-terminal free carboxyl functional group, resins such as 2-chlorotrityl chloride resin, Wang resin, or Merrifield resin may be used to form an ester bond with Fmoc-amino acid. Most of these ester-linked Fmoc-amino acid resin types are commercially available from various sources and are widely used (where possible).

[0172] Synthesis of disulfide-cyclized peptides Linear derivatives of cyclic disulfide peptide amides were assembled on solid-phase peptide synthesizers using Fmoc chemistry. The Fmoc-Rink amide resin was placed in a reaction vessel and swollen with NMP. It was treated with 20% piperidine in NMP for 15 minutes, followed by three washes with NMP. The resin tested positive in the Kaiser test (Kaiser, E., Colescot, RL, Bossinge, CD). & Cook, PI, Anal. Biochem., 1990, 34:595-598). This was resuspended in NMP and mixed with the requisite first C-terminal Fmoc-amino acid derivative and HOBt. HBTU reagent and DIPEA were added to initiate the coupling reaction. After 2-3 hours of mixing, completion of the coupling was confirmed by performing a negative Kaiser test on a small aliquot of resin recovered from the reaction mixture. The resin was then washed three times with NMP, after which the Fmoc group was removed as described above. The entire cycle was then repeated with the second C-terminal Fmoc-amino acid derivative as described, followed by the same reaction cycle with each successive incoming amino acid. In the case of peptides with an N-terminal acetyl group, the Fmoc-deprotected peptide resin was treated with acetic anhydride and pyridine for 10 minutes. Resins that tested negative in the Kaiser test were washed with NMP and dichloromethane and dried under reduced pressure. Fmoc-amino acid derivatives were used in the synthesis of these peptides. The trifunctional amino acid derivatives used were: Fmoc-Cys(Trt)-OH, Fmoc-Trp(Boc)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-hCys(Trt)-OH, Fmoc-Pen(Trt)-OH, Fmoc-Glu(OBut)-OH, and Fmoc-D-Phe-OH.

[0173] To cleave the peptide from the resin and deprotect the side chain functions, the peptide resin was taken up in 2% TIS / 5% water / 5% DTT (w / v) / 88% TFA. The solution was mixed for 3.5 hours and then filtered. The filtrate was mixed with cold, anhydrous ethyl ether. The precipitate was collected by centrifugation. The solvent was decanted, and the peptide pellet was resuspended in fresh ether. The ether workup was repeated two more times. The peptide was dried under reduced pressure. The crude linear peptide product was diluted with 5% acetic acid to a concentration of 2 mg / mL, and 0.5 M iodine / methanol was added dropwise and stirred vigorously until a persistent pale yellow solution was obtained. The solution was stirred for an additional 10 min. 1 M sodium thiosulfate was then added with mixing to quench the excess iodine. The cyclized peptide solution was lyophilized, and the crude powder was purified by preparative HPLC using a reverse-phase C-18 column. The purified product fractions were pooled and lyophilized. The peptides were analyzed by mass spectrometry using electrospray ionization techniques to identify their exact masses.

[0174] Synthesis of lactam-cyclized peptides Cyclic lactam peptides were also synthesized by standard solid-phase peptide synthesis. Fmoc-Dpr(Mtt)-BHA resin for peptides with C-terminus Dpr and Fmoc-Abu(Mtt)-BHA resin for peptides with C-terminus Abu were transferred to a solid-phase peptide synthesizer reactor. The Fmoc group was removed as described above, and the next Fmoc-protected amino acid (e.g., Fmoc-Trp(Boc)-OH) was coupled to the resin by standard coupling procedures. The protecting groups were removed, and the remaining amino acids were added individually in the appropriate sequence by repeating the coupling and deprotection procedures until the amino acid sequence was complete. For glutamic acid or aspartic acid, coupling Fmoc-Glu(OPip) or Fmoc-Asp(OPip) was used. The fully N-terminally coupled peptide was then acetylated by the method previously described for the peptide disulfide series. The orthogonal protected side chain was removed; for example, the orthogonal protected side chain of Glu as a 2-phenylisopropyl (OPip) ester, or 4-methyltrityl (Mtt) ester. The peptide resin containing the orthogonally protected side chain of Dpr was cleaved by treatment with 1% trifluoroacetic acid (TFA) in dichloromethane. The protected peptide resin was suspended in NMP and treated with HBTU / DIPEA. After cyclization (negative Kaiser test), the peptide resin was washed with DCM and dried. The cyclic peptide, along with any remaining protecting groups, was cleaved from the resin using trifluoroacetic acid (TFA) in the presence of water and 1,2-ethanedithiol (EDT). The product was precipitated by the addition of cold anhydrous ether and collected by centrifugation. Final purification was performed by reversed-phase HPLC using a reversed-phase C-18 column. The purified peptide was collected by lyophilization using electrospray methodology, and its mass was analyzed by mass spectrometry.

[0175] Those skilled in the art can modify the synthetic polypeptides of formulas (I and II) described herein.

[0176] Radioligand binding assay: The binding constant (K) for displacing the radiolabeled ligand from the receptor of the cyclic peptide of formula (I or II) d ) or inhibitory concentration (IC 50 In quantifying ), receptor binding assays can be performed by any means known in the art.

[0177] As an example, cell membrane preparations for binding assays are prepared from CHO-K1 cells transfected to stably express hMC receptor subtypes 1, 3, 4, or 5. 125 I](Tyr 2 )-(Nle 4 -D-Phe 7 )-α-MSH([ 125 Competitive inhibition of [I]-NDP-α-MSH binding is performed in polypropylene 96-well plates. Briefly, cell membranes (1-10 μg protein / well) prepared as described above were incubated with test compounds and 0.1-0.3 nM [I] in 50 mM Tris-HCl (pH 7.4) containing 0.2% BSA, 5 mM MgCl, 1 mM CaCl, and 0.1 mg / mL bacitracin. 125 The mixture was incubated at 37°C for approximately 120 minutes with increasing concentrations of [I]-NDP-α-MSH. 125 I]-NDP-α-MSH ligand release [ 125 The radioactivity was separated from [I]-NDP-α-MSH and filtered using GF / C glass fiber filter plates (Unifilter®, Meriden, Connecticut, USA) presoaked in 0.1% (w / v) polyethyleneimine (PEI). Filters were washed three times with 50 mM Tris-HCl (pH 7.4) at approximately 0-4°C and assayed for radioactivity. Binding data were analyzed by computer-assisted nonlinear regression analysis.

[0178] Cyclic AMP stimulation assay In functional assays, confirmation of the agonist or antagonist status of the cyclic peptides of the polypeptides of formula (I and II) is carried out using methods known in the art.

[0179] Electrochemiluminescence (ECL) assay Peptide-mediated stimulation of intracellular cyclic AMP (cAMP) levels was quantified in a dose-dependent manner using an electrochemiluminescence (ECL) assay (Meso Scale Discovery, Gaithersburg, MD, USA; hereafter referred to as "MSD"). Briefly, CHO-K1 cells stably expressing hMC receptor subtypes were suspended in RMPI 1640® assay buffer (RMPI 1640 buffer) containing 0.5 mM IBMX and 0.2% protein cocktail (MSD Blocker A). Approximately 7,000 cells / well of transgenic CHO-K1 cells stably expressing hMC receptor subtypes 1, 3, 4, or 5 were sorted into 384-well multi-array plates (MSD) containing integrated carbon electrodes and coated with anti-cAMP antibody. Increasing concentrations of test compound were added, and the cells were incubated at 37°C for approximately 40 minutes. Cell lysis buffer (HEPES-buffered saline with MgCl2, and Triton X-1000) containing 0.2% protein cocktail and 2.5 nM TAG™ ruthenium-labeled cAMP (MSD) was added. X-100® (pH 7.3) is added and the cells are incubated at room temperature for approximately 90 minutes. At the end of the second incubation period, reading buffer (a Tris-buffered solution containing ECL coreactants and Triton X-100 (pH 7.8)) is added, and cAMP levels in the cell lysates are immediately quantified by ECL detection using a Sector Imager 6000 Reader® (MSD). Data are analyzed by computer-assisted nonlinear regression analysis (XLfit; IDBS) and reported as an EC50 value. EC50 represents the concentration of agonist compound required to obtain 50% of the maximum response (e.g., 50% of the maximum level of cAMP quantified using the assay described above).

[0180] cAMP measurement assay Human MC4-R transfected cells are grown to confluence in 96-well plates (approximately 250,000 cells / well). The cells are treated in triplicate with 0.2 mM isobutylmethylxanthine (IBMX) and a gradient of peptide, or alternatively, peptide in the presence of 20 nM NDP-MSH. Cells similarly treated with 20 nM NDP-MSH alone serve as a positive control in a volume of 200 μL. A buffer blank also serves as a negative control. After incubation at 37°C for 1 hour, cells are lysed by adding 50 μL of cell lysis buffer. The total amount of cAMP accumulated in 250 μL of incubation medium is quantified using a commercially available low-pH cAMP assay kit (Amersham BioSciences) according to the kit supplier's protocol. Peptides that show accumulation of cAMP in the same range or greater than that of α-MSH as a positive control are considered agonists. Agonist data are plotted, curves are fitted, and EC50 values ​​are determined. Peptides that show accumulation in the same range as the negative control (buffer blank in the absence of α-MSH) are ineffective at the test concentration. Peptides that show attenuation of accumulation when α-MSH is also present in the assay and there is inhibition in cAMP are considered antagonists. Similar assays can also be performed using hMC-1R, hMC-3R, and hMC-5R cells.

[0181] Measurement of cAMP accumulation with the β-galactosidase (β-Gal) reporter system A chemiluminescent readout system using an enzyme fragment complementation (EFC) system containing β-galactosidase (β-Gal) was used as the functional reporter system. This assay system is compatible with various melanocortin receptor systems and is commercially available as the cAMP Hunter GPCR assay system from Discoverx Corp (based in Fremont, CA). This assay uses the β-Gal enzyme, which is split into two complementary parts: an enzyme acceptor EA and an enzyme donor ED. The ED part fused to cAMP competes with cAMP produced by the cells for binding to a cAMP-specific antibody. EA is then added to form active β-Gal with any unbound ED-cAMP. This active enzyme then converts a chemiluminescent substrate to generate an output signal, which is recorded using a standard microplate reader.

[0182] Briefly, 10,000 cells / well were plated overnight, and then each well (incubated with 10 μL of assay buffer) was incubated with 4-fold serial dilutions of test compound in cell assay buffer (5 μL) and cAMP antibody reagent (5 μL) for 30 minutes at 37°C. Subsequently, 20 μL of cell lysis buffer containing ED-cAMP conjugated enzyme fragment and reporter substrate (Emerald II-Galacton Star, 5:1) was added and incubated for 60 minutes at room temperature. Subsequently, 20 μL of EAβ-Gal fragment reagent was added and incubated for an additional 120 minutes at room temperature, after which chemiluminescence was measured using a plate reader (Envision).

[0183] EC-50 data for exemplary polypeptides of structural formulas I and II are shown below.

[0184] Examples: EC50 values ​​and selectivity. [Table 2]

[0185] equivalent The disclosures of all patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety. While the present invention has been disclosed with respect to certain embodiments, it will be apparent that others skilled in the art may devise other embodiments and variations of the present invention without departing from the true spirit and scope of the invention. The appended claims are intended to be construed to include all such embodiments and equivalent variations. The present invention provides, for example, the following items. (Item 1) A compound of formula I, [ka] wherein Xxx is Asn, Gln, Ser, or Thr; A1 is H or Ac; A2 is OH or NH2, and Yyy is Lys, Arg, D-Lys or D-Arg, or A compound that is a pharmaceutically acceptable salt, single stereoisomer, mixture of stereoisomers, ester, tautomer, or prodrug thereof. (Item 2) The compound has formula II [ka] wherein Xxx is Asn, Gln, Ser, or Thr; A1 is H or Ac; A2 is OH or NH2, and Yyy is Lys, Arg, D-Lys or D-Arg) The method according to item 1, wherein the compound is (Item 3) The compound of formula 1, wherein the compound comprises any one of SEQ ID NOS: 1 to 64. (Item 4) A pharmaceutical composition comprising a compound according to any one of items 1 to 3 and a pharmaceutically acceptable carrier. (Item 5) 4. A unit dosage amount of any of the compounds according to items 1 to 3, the unit dosage amount containing 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 or 100 mg of the compound. (Item 6) 6. The unit dosage of item 5, containing 0.5 mg, 1.0 mg, or 1.5 mg of the compound. (Item 7) The unit dosage according to any one of items 5 to 6, suitable for injection (e.g., subcutaneous injection). (Item 8) 8. The unit dosage of any one of items 5 to 7, disposed in a delivery device suitable for injection (e.g., subcutaneous injection). (Item 9) A method for treating a condition or disorder in a subject in need thereof, the method comprising administering a therapeutically effective amount of an MC4R agonist according to any one of items 1 to 3. (Item 10) 10. The method of claim 9, comprising eliciting an agonist effect from a melanocortin receptor in the subject. (Item 11) 10. The method of claim 9, comprising administering the MC4R agonist to elicit an agonist effect from the melanocortin receptor in the subject. (Item 12) 10. The method of item 9, wherein the disorder is a metabolic disease or medical condition accompanied by weight gain, such as obesity, an eating disorder, or Prader-Willi syndrome. (Item 13) 10. The method of claim 9, wherein the MC4R agonist is administered in an amount sufficient to reduce food intake, reduce body weight, or both, in the subject. (Item 14) 10. The method of claim 9, wherein the MC4R agonist is administered in an amount sufficient to reduce appetite without compromising body weight in the subject. (Item 15) The method of item 9, wherein a sufficient amount of the MC4R agonist is administered to ameliorate or improve clinical symptoms or indications of obesity, type II diabetes, pre-diabetic conditions, hemoglobin A1C (Hb1Ac) blood levels greater than 6%, hyperinsulinemia, hyperlipidemia, insulin insensitivity or glucose intolerance; to delay, inhibit or prevent the progression of aspects of metabolic syndrome, obesity and / or obesity-related indications; or to partially or completely delay, inhibit or prevent the onset or progression of obesity or obesity-related indications. (Item 16) 10. The method of item 9, wherein the condition or disorder is obesity or an obesity-related disorder, such as Prader-Willi syndrome, reduced food intake, or weight loss in a subject in need thereof. (Item 17) 17. The method of any one of items 1 to 16, comprising administering to the subject a unit dosage of the agonist suitable for injection (e.g., subcutaneous injection). (Item 18) 7. The method of claim 6, wherein the unit dosage is disposed in a delivery device, such as a syringe (e.g., a pre-filled syringe), an implantable device, a needleless hypodermic injection device, an infusion pump (e.g., an implantable infusion pump), or an osmotic delivery system. (Item 19) 19. The method according to any one of items 1 to 18, wherein the agonist is administered subcutaneously, for example by subcutaneous injection. (Item 20) 20. The method of any one of items 1-19, wherein the agonist is administered daily for at least 3 weeks, such as at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 weeks or more, or for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months or more, or for at least 1, 2, 3, 4, or more years. (Item 21) 21. The method of any one of items 1 to 20, wherein administration of the compound reduces the body weight of the subject. (Item 22) 22. The method of any one of items 1 to 21, wherein the subject is obese (e.g., severely obese). (Item 23) The method according to any one of Items 1 to 22, wherein the subject has early-onset severe obesity. (Item 24) 24. The method according to any one of items 1 to 23, wherein the subject is in a hyperphagic state. (Item 25) the subject's body mass index (BMI) prior to administration of the agonist (e.g., at the time the agonist is prescribed or first administered) is 25 kg / m 2 Over (e.g., 25 kg / m 2 More than 30kg / m 2 More than 31kg / m 2 More than 32kg / m 2 More than 33kg / m 2 More than 34kg / m 2 More than 35kg / m 2 More than 36kg / m 2 More than 37kg / m 2 More than 38kg / m 2 More than 39kg / m2 More than 40kg / m 2 More than 41kg / m 2 More than 42kg / m 2 More than 43kg / m 2 More than 44kg / m 2 More than 45kg / m 2 More than 46kg / m 2 More than 47kg / m 2 More than 48kg / m 2 More than 49kg / m 2 More than 50kg / m 2 25. The method according to any one of items 1 to 24, wherein the value is equal to or greater than the value of the reference value. (Item 26) 26. The method of any one of items 1 to 25, wherein the subject has failed one or more previous therapies (e.g., exercise, diet, bariatric surgery or vertical band gastroplasty, or behavioral therapy) prior to administering the agonist (e.g., at the time the agonist is prescribed or first administered). (Item 27) 27. The method of any one of items 1 to 26, wherein administration of the agonist results in a decrease in the subject's food intake compared to a control (e.g., the subject's food intake before treatment), e.g., when the food intake is measured as daily food intake over a 24-hour or week period. (Item 28) The agonist has the sequence 001554C: Ac-Arg-(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 1), 001555C: Ac-Arg-(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 2), 001556C: Ac-Arg-(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 3), 001574C: Ac-Arg-(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 4), 001576C: Ac-Arg-(Glu-Gln-D-Phe-Arg-Trp-Apr)-NH2 (SEQ ID NO: 5), Ac-Arg-(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 6), H-Arg-(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 7), H-Arg-(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 8), Ac-D-Arg-(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 9), HD-Arg-(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 10), Ac-D-Arg-(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 11), HD-Arg-(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 12), Ac-Lys-(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 13), Ac-Lys-(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 14), H-Lys-(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 15), H-Lys-(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 16), Ac-D-Lys-(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 17), HD-Lys-(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 18), Ac-D-Lys-(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 19), HD-Lys-(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 20), Ac-Arg-(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 21), H-Arg-(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 22), H-Arg-(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 23), Ac-D-Arg-(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 24), HD-Arg-(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 25), Ac-D-Arg-(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 26), HD-Arg-(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 27), Ac-Lys-(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 28), Ac-Lys-(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 29), H-Lys-(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 30), H-Lys-(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 31), Ac-D-Lys-(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 32), HD-Lys-(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 33), Ac-D-Lys-(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 34), HD-Lys-(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 35), Ac-Arg-(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 36), H-Arg-(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 37), H-Arg-(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 38), Ac-D-Arg-(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 39), HD-Arg-(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 40), Ac-D-Arg-(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 41), HD-Arg-(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 42), Ac-Lys-(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 43), Ac-Lys-(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 44), H-Lys-(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 45), H-Lys-(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 46), Ac-D-Lys-(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 47), HD-Lys-(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 48), Ac-D-Lys-(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 49), HD-Lys-(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 50), Ac-Arg-(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 51), H-Arg-(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 52), H-Arg-(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 53), Ac-D-Arg-(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 54), HD-Arg-(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 55), Ac-D-Arg-(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 56), HD-Arg-(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 57), Ac-Lys-(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 58), Ac-Lys-(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 59), H-Lys-(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 60), H-Lys-(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH (SEQ ID NO: 61), Ac-D-Lys-(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 62), HD-Lys-(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 63), Ac-D-Lys-(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 64) or HD-Lys-(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2 (SEQ ID NO: 65) 28. The method according to any one of items 1 to 27, comprising:

Claims

[Claim 1] A kit or method as described in the specification.

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