Developing SRX246 for Stress-Related Affective Illness

Stress-related affective illness is the collective term for emotional illnesses caused by chronic stress, such as anxiety and depression. Long-term stress leads to many physical, behavioral, mental and emotional health problems. These stress effects on the human body are caused when the generalized physiological response to stressors is constantly turned on. This “fight-or-flight” response happens because of a cascade of hormones released when the hypothalamus receives the stress signal and passes it along to the pituitary and adrenal cortex. As many as 40 million Americans have symptoms of anxiety and depression, resulting in varying levels of debility. These researchers are developing a treatment for depression and anxiety. The new therapy operates by blocking a hormone called vasopressin that drives the hypothalamus-pituitary-adrenal cortex response to chronic stress.

Scientific Synopsis

A compelling case for the potential utility of vasopressin (AVP) antagonists as a novel therapeutic class for the treatment of stress-related affective illness has emerged based on observations in depressed individuals, findings in animal models of anxiety and depression, and an understanding of changes in hypothalamic-pituitary-adrenal (HPA) axis regulation under chronic stress. This proposal seeks support for the continued development of SRX246.HCl, a novel vasopressin 1a (V1a) receptor antagonist that has shown efficacy in preclinical animal models of anxiety and depression, good plasma bioavailability and CNS penetration following oral administration, a strong safety profile, and high affinity and selectivity for the target receptor.

The scientific bases for V1a antagonists as a pharmacotherapy for anxiety and depression include (1) the neuroadaptation and dysregulation of HPA function that accompanies chronic stress in affected humans and in animal models of anxiety and depression; (2) recognition that AVP, not CRF, drives HPA function associated with chronic psychological stress; (3) the CNS localization of V1a receptors in limbic system regions involved in HPA regulation and control of social behaviors; and (4) preclinical data with SRX246 showing efficacy in animal models employed as screens for anxiolytic/antidepressant activity. The public health need for new pharmaceutical treatments for stress-related affective illness is well documented. Existing pharmacotherapies for both indications are not uniformly effective and frequently have undesirable side effects. These limitations demonstrate that a new treatment approach through V1a receptor antagonism may offer significant opportunities for improved outcomes.

Lead Collaborator

Lehigh University, Bethlehem, Pennsylvania
Neal G. Simon, Ph.D.

Public Health Impact

Anxiety and depression affect more than 40 million Americans each year and carry a conservatively estimated annual total economic burden of $125 billion. BrIDGs support for SRX246 will complement existing investments and significantly advance the likelihood of additional private sector investment to accelerate the commercialization of this agent.


The investigator successfully filed an Investigational New Drug (IND) application using BrIDGs data and initiated clinical testing. SRX246 eventually entered Phase II clinical trials in patients with intermittent explosive disorder.

Project Details

  • Synthesis of Good Manufacturing Practice (GMP) material
  • Formulation development
  • Investigational New Drug (IND)-directed toxicology