Crf1 receptor antagonists for the treatment of congenital adrenal hyperplasia

Abstract

CRF 1 receptor antagonists have the potential to directly inhibit ACTH release in patients with CAH and thereby allow normalization of androgen production while using lower, more physiologic doses of hydrocortisone, and thus reducing treatment-associated side effects.

I claim the following: 
     
         1 . A method for treating Congenital Adrenal Hyperplasia (CAH) by administering to a subject in need thereof a CRF 1  receptor antagonist having a dissociation half-life in excess of 30 minutes. 
     
     
         2 . The method of  claim 1  wherein the CRF 1  receptor antagonist has a dissociation half-life in excess of 40 minutes. 
     
     
         3 . The method of  claim 1  wherein the CRF 1  receptor antagonist has a dissociation half-life in excess of 50 minutes. 
     
     
         4 . The method of  claim 1  wherein the CRF 1  receptor antagonist is Compound I (NBI-77860; 2,5-dimethyl-3-[2-methyl-4-(methyloxy)phenyl]-N-[(1S)-1-(3-methyl-1,2,4-oxadiazol-5-yl)propyl]pyrazolo[1,5-a]pyrimidin-7-amine). 
     
     
         5 . The method of  claim 1  wherein the CRF 1  receptor antagonist is NBI-30775, NBI-34041, SSR-126374, SSR-125543, antalarmin (N-butyl-N-ethyl-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidin-4-amine), or DMP904. 
     
     
         6 . The method of any one of  claims 1 - 5  wherein the CRF 1  receptor antagonist is administered at bedtime. 
     
     
         7 . The method of any one of  claims 1 - 5  wherein the CRF 1  receptor antagonist is administered at or before the expected circadian release of ACTH. 
     
     
         8 . The method of  claim 7  wherein the CRF 1  receptor antagonist is administered 3-4 hours before the expected circadian release of ACTH. 
     
     
         9 . A method for reducing 17-OHP and ACTH levels in a subject who has Congenital Adrenal Hyperplasia (CAH), said method comprising administering to the subject a CRF 1  receptor antagonist at bedtime. 
     
     
         10 . The method of  claim 9 , wherein the CRF 1  receptor antagonist is administered at or before the expected circadian release of ACTH. 
     
     
         11 . The method of  claim 9 , wherein the CRF 1  receptor antagonist is administered 3-4 hours before the expected circadian release of ACTH. 
     
     
         12 . The method of any one of  claims 9 - 11 , wherein the CRF 1  receptor antagonist is Compound I (NBI-77860; 2,5-dimethyl-3-[2-methyl-4-(methyloxy)phenyl]-N-[(1S)-1-(3-methyl-1,2,4-oxadiazol-5-yl)propyl]pyrazolo[1,5-a]pyrimidin-7-amine). 
     
     
         13 . The method of any one of  claims 9 - 11 , wherein the CRF 1  receptor antagonist is NBI-30775, NBI-34041, SSR-126374, SSR-125543, antalarmin (N-butyl-N-ethyl-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidin-4-amine), or DMP904. 
     
     
         14 . A CRF 1  receptor antagonist for use in treating Congenital Adrenal Hyperplasia (CAH), wherein the CRF 1  receptor antagonist has a dissociation half-life in excess of 30 minutes. 
     
     
         15 . The CRF 1  receptor antagonist of  claim 14 , wherein the CRF 1  receptor antagonist has a dissociation half-life in excess of 40 minutes. 
     
     
         16 . The CRF 1  receptor antagonist of  claim 14 , wherein the CRF 1  receptor antagonist has a dissociation half-life in excess of 50 minutes. 
     
     
         17 . The CRF 1  receptor antagonist of  claim 14 , wherein the CRF 1  receptor antagonist is Compound I (NBI-77860; 2,5-dimethyl-3-[2-methyl-4-(methyloxy)phenyl]-N-[(1S)-1-(3-methyl-1,2,4-oxadiazol-5-yl)propyl]pyrazolo[1,5-a]pyrimidin-7-amine). 
     
     
         18 . The CRF 1  receptor antagonist of  claim 14 , wherein the CRF 1  receptor antagonist is NBI-30775, NBI-34041, SSR-126374, SSR-125543, antalarmin (N-butyl-N-ethyl-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidin-4-amine), or DMP904. 
     
     
         19 . The CRF 1  receptor antagonist of any one of  claims 14 - 18 , wherein the CRF 1  receptor antagonist is suitable for administration at bedtime. 
     
     
         20 . The CRF 1  receptor antagonist of any one of  claims 14 - 18 , wherein the CRF 1  receptor antagonist is suitable for administration at or before the expected circadian release of ACTH. 
     
     
         21 . The CRF 1  receptor antagonist of any one of  claims 14 - 18 , wherein the CRF 1  receptor antagonist is suitable for administration 3-4 hours before the expected circadian release of ACTH.