Corticotropin releasing factor receptor antagonists
The present invention provides novel pharmaceutical compositions comprising -(4-Chloro-2-(morpholin-4-yl)thiazol-5-yl)-7-(1-ethylpropyl)-2,5-dimethylpyrazolo(1,5-a)pyrimidine and methods of using the same for the treatment of Congenital adrenal hyperplasia (CAH).
1. A method for treating congenital adrenal hyperplasia (CAH) in a human, comprising:
administering to said human a therapeutically-effective amount of a CRF 1 receptor antagonist or a pharmaceutically acceptable salt thereof,
wherein said human has received or has been previously determined to receive a first dose of a glucocorticoid, and
administering to said human a second dose of a glucocorticoid, wherein said second dose of a glucocorticoid is reduced compared to said first dose of a glucocorticoid,
wherein an androstenedione (A4) level in said subject is reduced from baseline, or
wherein an adrenocorticotropic hormone (ACTH) level in said subject is reduced from baseline, or
wherein a 17-hydroxyprogesterone (17-OHP) level in said subject is reduced from baseline,
wherein said CRF1 receptor antagonist or a pharmaceutically acceptable salt thereof is administered at a dose between about 50 mg/day and about 200 mg/day, and wherein said CRF1 receptor antagonist is stable for storage for a minimum of six months.
2. The method of claim 1 , wherein said A4 level, said ACTH level, or said 17-OHP level in said human is reduced by at least 5% from baseline.
3. The method of claim 1 , wherein said A4 level, said ACTH level, or said 17-OHP level in said human is reduced by at least 10% from baseline.
4. The method of claim 1 , wherein said A4 level, said ACTH level, or said 17-OHP level in said human is reduced by at least 15% from baseline.
5. The method of claim 1 , wherein said A4 level, said ACTH level, or said 17-OHP level in said human is reduced by at least 20% from baseline.
6. The method of claim 1 , wherein said A4 level, said ACTH level, or said 17-OHP level in said human is reduced by at least 25% from baseline.
7. The method of claim 1 , wherein said A4 level, said ACTH level, or said 17-OHP level in said human is reduced from baseline and is maintained at a reduced level post 24 hours.
8. The method of claim 1 , wherein said A4 level, said ACTH level, or said 17-OHP level in said human is reduced from baseline and is maintained at a reduced level post 4 weeks.
9. The method of claim 1 , wherein said A4 level, said ACTH level, or said 17-OHP level in said human is reduced from baseline and is maintained at a reduced level post 6 weeks.
10. The method of claim 1 , wherein said administering of said first dose of said glucocorticoid is concurrently or sequentially within 2 hours of said administering of said therapeutically-effective amount of a CRF 1 receptor antagonist or a pharmaceutically acceptable salt thereof.
11. The method of claim 1 , wherein said CRF 1 receptor antagonist or a pharmaceutically acceptable salt thereof is Compound 1:
or a pharmaceutically acceptable salt thereof.
12. The method of claim 1 , wherein said glucocorticoid is selected from beclomethasone, betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, and triamcinolone.
13. The method of claim 1 , wherein said glucocorticoid is hydrocortisone.
14. The method of claim 1 , wherein said first dose of said glucocorticoid comprises a supraphysiologic amount of said glucocorticoid.
15. The method of claim 1 , wherein said second dose of said glucocorticoid comprises a physiologic amount of said glucocorticoid.
16. The method of claim 1 , wherein said CRF1 receptor antagonist or a pharmaceutically acceptable salt thereof is orally administered.
17. The method of claim 16 , wherein said oral administration is once a day.
18. The method of claim 16 , wherein said oral administration is twice a day.
19. The method of claim 1 , wherein said first dose is a first daily dose and said second dose is a second daily dose.
20. The method of claim 1 , wherein said second dose of said glucocorticoid is at least about 5%, at least about 10%, or at least about 20% lower than said first dose of said glucocorticoid.
21. The method of claim 1 , wherein said CRF1 receptor antagonist is stable between about 25° C. and about 40° C.