The present invention relates to RNAi agents, e.g., double-stranded RNAi agents, targeting the angiotensinogen (AGT) gene, and methods of using such RNAi agents to inhibit expression of AGT and methods of treating subjects having an AGT-associated disorder, e.g., hypertension.

Novel crystalline Forms of trisodium [3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butyl carbamoyl) propionate-(S)-3′-methyl-T-(pentanoyl{2″-(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)butyrate] hydrate, methods for their preparation, pharmaceutical compositions comprising these new forms, and use of them for treating or delaying progression or onset of diseases or disorders related to activity of angiotensin receptor 1 (AT1) blockage and neprilysin (NEP) inhibition, such as heart failure, are disclosed.

The present invention is directed to antibodies and fragments thereof having binding specificity for ACTH. Another embodiment of this invention relates to the antibodies binding fragments thereof described herein, comprising the sequences of the V.sub.H, V.sub.L and/or CDR polypeptides described herein, and the polynucleotides encoding them. The invention also contemplates conjugates of anti-ACTH antibodies and binding fragments thereof conjugated to one or more functional or detectable moieties. The invention further contemplates methods of making said anti-ACTH antibodies and binding fragments thereof. Embodiments of the invention also pertain to the use of anti-ACTH antibodies and binding fragments thereof for the diagnosis, assessment, prevention and treatment of diseases and disorders associated with ACTH, such as Cushing's Disease, Cushing's Syndrome, Parkinson's disease, obesity, diabetes, sleep disorders depression, anxiety disorders, cancer, muscle atrophy, hypertension, hyperinsulinemia, cognitive dysfunction, Alzheimer's disease, galactorrhea, stress related conditions, cardiac conditions, metabolic syndrome, hyperaldosteronism, Conn's syndrome and familial hyperaldosteronism.

The present invention relates to compounds of formula I: ##STR00001##
and pharmaceutically acceptable salts thereof, wherein R.sup.1, R.sup.2 and R.sup.3, are as defined herein. The invention also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.

The present invention is directed to antibodies and fragments thereof having binding specificity for ACTH. Another embodiment of this invention relates to the antibodies binding fragments thereof described herein, comprising the sequences of the V.sub.H, V.sub.L and/or CDR polypeptides described herein, and the polynucleotides encoding them. The invention also contemplates conjugates of anti-ACTH antibodies and binding fragments thereof conjugated to one or more functional or detectable moieties. The invention further contemplates methods of making said anti-ACTH antibodies and binding fragments thereof. Embodiments of the invention also pertain to the use of anti-ACTH antibodies and binding fragments thereof for the diagnosis, assessment, prevention and treatment of diseases and disorders associated with ACTH, such as Cushing's Disease, Cushing's Syndrome, Parkinson's disease, obesity, diabetes, sleep disorders depression, anxiety disorders, cancer, muscle atrophy, hypertension, hyperinsulinemia, cognitive dysfunction, Alzheimer's disease, galactorrhea, stress related conditions, cardiac conditions, metabolic syndrome, hyperaldosteronism, Conn's syndrome and familial hyperaldosteronism.

The invention provides novel compounds having the general formula (I)

##STR00001##

wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.15, R.sup.16, R.sup.17 and n are as described herein, compositions including the compounds and methods of using the compounds.

The invention provides novel compounds having the general formula (I)

##STR00001##

wherein R.sup.1, R.sup.2 and n are as described herein, compositions including the compounds and methods of using the compounds.

The invention provides novel compounds having the general formula (I)

##STR00001##

wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17 and m are as described herein, compositions including the compounds and methods of using the compounds.

The present invention is based, in part, on our discovery that certain types of therapeutic agents can be used in combination to treat a variety of neuropsychiatric and related disorders, including addiction (e.g., to a substance or to an activity) as well as to alleviate some of the symptoms experienced during menopause or associated with the menstrual cycle. Regardless of the precise formulation, the compositions of the invention can include at least one active ingredient that targets the hypothalamopituitary-adrenal (HPA) axis and at least one active ingredient that targets the prefrontal cortex. Either or both of these types of agents can be combined with an agent that inhibits activity in the sympathetic nervous system. Thus, the compositions or combination pharmacotherapies can also include an agent that inhibits a beta-adrenergic receptor or that otherwise acts as an anti-hypertensive or anxiolytic agent.

Methods and compositions are provided for treatment of disorders associated with aberrant adrenal cortex cell behavior, including (but not limited to) treatment of adrenocortical carcinoma (ACC), Cushing's syndrome and/or pituitary ACTH excess (Cushing's Disease). Such methods involve administration of an effective amount N-(2,6-bis(1-methylethyl)phenyl)-N′-((1-(4-(dimethylamino)phenyl)cyclopentyl)-methyl)urea hydrochloride to the patient.