The poor aqueous solubility of progesterone (PROG) limits its potential use as a therapeutic
agent. We designed and tested EIDD-1723, a novel water-soluble analog of PROG with
>100-fold higher solubility than that of native PROG, as candidate for development
as a field-ready treatment for traumatic brain injury (TBI). The pharmacokinetic effects
of EIDD-1723 on morphological and functional outcomes in rats with bilateral cortical
impact injury were evaluated. Following TBI, 10-mg/kg doses of EIDD-1723 or PROG were
given intramuscularly (i.m.) at 1, 6 and 24 h post-injury, then daily for the next
6 days, with tapering of the last 2 treatments. Rats were tested pre-injury to establish
baseline performance on grip strength and sensory neglect, and then retested at 4,
9 and 21 days post-TBI. Spatial learning was evaluated from days 11-17 post-TBI. At
22 days post-injury, rats were perfused and brains extracted and processed for lesion
size. For the edema assay the animals were killed and brains removed at 24 h post-injury.
EIDD-1723 significantly reduced cerebral edema and improved recovery from motor, sensory
and spatial learning deficits as well as, or better than, native PROG. Pharmacokinetic
investigation after a single i.m. injection in rats revealed that EIDD-1723 was rapidly
converted to the active metabolite EIDD-036, demonstrating first-order elimination
kinetics and ability to cross the blood-brain barrier. Our results suggest that EIDD-1723
represents a substantial advantage over current PROG formulations because it overcomes
storage, formulation and delivery limitations of PROG and can thereby reduce the time
between injury and treatment.