US2002137664A1PendingUtilityA1

Substituted piperidines as melanocortin-4 receptor agonists

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Assignee: MERCK & CO INCPriority: Jun 4, 1999Filed: Nov 21, 2001Published: Sep 26, 2002
Est. expiryJun 4, 2019(expired)· nominal 20-yr term from priority
Inventors:Raman K. BakshiKhaled BarakatRavi NargundBrenda PaluckiArthur A. PatchettIyassu SebhatZhixiong YeLeonardus H. T. Van Der Ploeg
A61P 3/04A61P 3/10A61K 31/4985C07D 401/14C07D 413/14A61P 15/00A61K 31/4725C07D 249/08C07D 417/14C07D 231/12C07D 471/04C07D 401/12C07D 233/56A61P 15/10C07D 405/14
47
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Claims

Abstract

Certain novel substituted piperidine compounds are agonists of the human melanocortin receptor(s) and, in particular, are selective agonists of the human melanocortin-4 receptor (MC-4R). They are therefore useful for the treatment, control, or prevention of diseases and disorders responsive to the activation of MC-4R, such as obesity, diabetes, sexual dysfunction, including erectile dysfunction and female sexual dysfunction. Also provided are methods of treating sexual dysfunction with a compound that is a selective agonist of MC-4R over any other human melanocortin receptor.

Claims

exact text as granted — not AI-modified
What is claimed is:  
     
         26 . A method of treating sexual dysfunction in a male or female subject which comprises administering to the subject in need thereof a therapeutically effective amount of a compound which is a human melanocortin-4 receptor (MC-4R) agonist wherein the binding of the compound to the human MC-4R is characterized by an IC 50  less than 30 nanomolar (nM) and the binding of the compound to the human MC-1R is characterized by an IC 50  greater than 30 nM.  
     
     
         27 . The method of claim  26  wherein the binding of the compound to the human MC-1R is characterized by an IC 50  greater than 100 nM.  
     
     
         28 . The method of claim  26  wherein the binding of the compound to the human MC-1R is characterized by an IC 50  greater than 1000 nM.  
     
     
         29 . The method of claim  26  wherein the binding of the compound to the human MC-1R is characterized by an IC 50  greater than 2100 nM.  
     
     
         30 . A method of treating sexual dysfunction in a male or female subject which comprises administering to the subject in need thereof a therapeutically effective amount of a compound which is a human MC-4R agonist wherein the binding of the compound to the human MC-4R is characterized by an IC 50  less than 30 nM and the binding of the compound to the human MC-3R is characterized by an IC 50  greater than 30 nM.  
     
     
         31 . The method of  claim 30  wherein the binding of the compound to the human MC-3R is characterized by an IC 50  greater than 100 nM.  
     
     
         32 . The method of  claim 30  wherein the binding of the compound to the human MC-3R is characterized by an IC 50  greater than 540 nM.  
     
     
         33 . A method of treating sexual dysfunction in a male or female subject which comprises administering to the subject in need thereof a therapeutically effective amount of a compound which is a human MC-4R agonist wherein the binding of the compound to the human MC-4R is characterized by an IC 50  less than 30 nM and the binding of the compound to the human MC-5R is characterized by an IC 50  greater than 30 nM.  
     
     
         34 . The method of  claim 33  wherein the binding of the compound to the human MC-5R is characterized by an IC 50  of greater than 100 nM.  
     
     
         35 . The method of  claim 33  wherein the binding of the compound to the human MC-5R is characterized by an IC 50  greater than 230 nM.  
     
     
         36 . The method of claim  26  wherein the compound is further characterized by binding to each of the human MC-2R, MC-3R, and MC-5R with an IC 50  greater than 30 nM.  
     
     
         37 . The method of claim  27  wherein the compound is further characterized by binding to each of the human MC-2R, MC-3R, and MC-5R with an IC 50  greater than 100 nM.  
     
     
         38 . The method of claim  28  wherein the compound is further characterized by binding to each of the human MC-2R and MC-3R with an IC 50  greater than 540 nM and binding to the MC-5R with an IC 50  greater than 230 nM.  
     
     
         39 . The method of  claim 36  wherein the compound is further characterized by binding to any other human melanocortin receptor with an 1C 50  greater than 30 nM.  
     
     
         40 . The method of  claim 37  wherein the compound is further characterized by binding to any other human melanocortin receptor with an 1C 50  greater than 100 nM.  
     
     
         41 . The method of  claim 38  wherein the compound is further characterized by binding to any other human melanocortin receptor with an IC 50  greater than 500 nM.  
     
     
         42 . A method of treating sexual dysfunction in a male or female subject which comprises administering to the subject in need thereof a therapeutically effective amount of a compound which is a human MC-4R agonist wherein the compound binds to the human MC-4R with a binding affinity at least 10-fold higher than the compound binds to each of the human MC-1R, MC-2R, MC-3R, and MC-5R.  
     
     
         43 . The method of  claim 42  wherein the compound binds to the human MC-4R with a binding affinity at least 100-fold higher than the compound binds to each of the human MC-1R, MC-2R, MC-3R, and MC-5R.  
     
     
         44 . The method of  claim 42  wherein the compound binds to the human MC-4R with a binding affinity at least 1000-fold higher than the compound binds to each of the human MC-1R and MC-2R, at least 580-fold higher than the compound binds to the human MC-3R, and at least 250-fold higher than the compound binds to the human MC-5R.  
     
     
         45 . A method of treating sexual dysfunction in a male or female subject which comprises administering to the subject in need thereof a therapeutically effective amount of a compound which is a human MC-4R agonist wherein the compound binds to the human MC-4R with a binding affinity at least 10-fold higher than the compound binds to any other human melanocortin receptor.  
     
     
         46 . The method of  claim 45  wherein the compound binds to the human MC-4R with a binding affinity at least 100-fold higher than the compound binds to any other human melanocortin receptor.  
     
     
         47 . A method of treating sexual dysfunction in a male or female subject which comprises administering to the subject in need thereof a therapeutically effective amount of a compound which is a human MC-4R agonist wherein the functional activity at the MC-4R is characterized by an EC 50  less than 10 nM and the functional activity at the MC-1R is characterized by an EC 50  greater than 10 nM.  
     
     
         48 . The method of  claim 47  wherein the functional activity of the compound at the MC-1R is characterized by an EC 50  greater than 100 nM.  
     
     
         49 . The method of  claim 47  wherein the functional activity of the compound at the MC-1R is characterized by an EC 50  greater than 1200 nM.  
     
     
         50 . A method of treating sexual dysfunction in a male or female subject which comprises administering to the subject in need thereof a therapeutically effective amount of a compound which is a human MC-4R agonist wherein the functional activity at the MC-4R is characterized by an EC 50  less than 10 nM and the functional activity at the MC-3R is characterized by an EC 50  greater than 10 nM.  
     
     
         51 . The method of  claim 50  wherein the functional activity of the compound at the MC-3R is characterized by an EC 50  greater than 100 nM.  
     
     
         52 . The method of  claim 50  wherein the functional activity of the compound at the MC-3R is characterized by an EC 50  greater than 1200 nM.  
     
     
         53 . A method of treating sexual dysfunction in a male or female subject which comprises administering to the subject in need thereof a therapeutically effective amount of a compound which is a human MC-4R agonist wherein the functional activity at the MC-4R is characterized by an EC 50  less than 10 nM and the functional activity at the MC-5R is characterized by an EC 50  greater than 10 nM.  
     
     
         54 . The method of  claim 53  wherein the functional activity of the compound at the MC-5R is characterized by an EC 50  greater than 100 nM.  
     
     
         55 . The method of  claim 53  wherein the functional activity of the compound at the MC-5R is characterized by an EC 50  greater than 520 nM.  
     
     
         56 . The method of  claim 47  wherein the compound is further characterized by having a functional activity at each of the human MC-2R, MC-3R, and MC-5R with an EC 50  greater than 10 nM.  
     
     
         57 . The method of  claim 48  wherein the compound is further characterized by having a functional activity at each of the human MC-2R, MC-3R, and MC-5R with an EC 50  greater than 100 nM.  
     
     
         58 . The method of  claim 49  wherein the compound is further characterized by having a functional activity at the human MC-2R and MC-3R with an EC 50  greater than 1200 nM and a functional activity at the human MC-5R with an EC 50  greater than 520 nM.  
     
     
         59 . A method of treating sexual dysfunction in a male or female subject which comprises administering to the subject in need thereof a therapeutically effective amount of a compound which is a human MC-4R agonist wherein the functional activity at the human MC-4R is characterized by an EC 50  at least 10-fold lower than the functional activity at each of the human MC-1R, MC-2R, MC-3R, and MC-5R.  
     
     
         60 . The method of  claim 59  wherein the functional activity at the human MC-4R is characterized by an EC 50  at least 100-fold lower than the functional activity at each of the human MC-1R, MC-2R, MC-3R, and MC-5R.  
     
     
         61 . A method for the oral treatment of sexual dysfunction in a male or female subject which comprises the oral administration to the subject in need thereof a therapeutically effective amount of a compound which is an agonist of the human MC-4R.  
     
     
         62 . The method of claim  61  wherein the compound is a selective agonist of the human MC-4R.  
     
     
         63 . The method of claim  61  wherein the sexual dysfunction is erectile dysfunction.

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