Non-steroidal mineralocorticoid receptor (MR) modulator

Preclinical pharmacology

AZD9977 is functional antagonist of the recombinant human, dog, mouse and rat MR ligand-binding domain in cell based reporter gene assays (IC50 sub-micromolar in all species).  In a diverse set of in vitro assays covering 185 distinct molecular targets (receptors [including other steroid receptors: PR, GR, ER, AR], ion channels, transporters and enzymes), a2A adrenoceptor antagonism was detected in the therapeutic range, but not confirmed in in vivo toxicology studies.

Oral administration of AZD9977 improves renal and cardiac pathology as well as kidney function in various rat and mouse PD and disease models with similar efficacy as eplerenone.  In contrast to eplerenone, and other known MR antagonists, AZD9977 has shown no or minimal effects on urinary or plasma electrolyte homeostasis in several pre-clinical models.

Safety and tolerability

AZD9977 has been administered orally to healthy volunteers in single doses up to 1200 mg with no treatment related adverse events.

Preclinical toxicology studies of up to 1 month duration have been completed.  AZD9977 was well tolerated up to a  ~10x safety margin, which is the maximal exposure achieved in rat.

Clinical pharmacology

AZD9977 was rapidly absorbed after oral administration in healthy volunteers with an observed PK profile suitable for further development and well aligned with predictions from preclinical data.  Maximum plasma concentrations occurred at a median of 1.0 hour and a terminal t1/2 of ~1.8h.

In a single-dose, randomized, placebo-controlled, crossover, proof-of-mechanism (PoM) urinary electrolyte study in healthy volunteers, AZD9977 (like eplerenone) reversed fludrocortisone-induced sodium retention.  This is in contrast to preclinical data in presence of aldosterone, but aligned with preclinical data in presence of fludrocortisone.

AZD9977 development has been paused for strategic reasons.

Suitable for and exclusions

Preclinical reprotoxicology data are not available for this compound. The inclusion of women of child-bearing potential using highly effective contraception in trials of modest size and duration could be considered based on the risk benefit and in accordance with territory specific requirements.

Preclinical and clinical safety studies to date support future clinical, most likely phase 1/1b studies, of £ 1 month duration.  Proposals that mechanistically differentiate AZD9977 from eplerenone in the clinic (e.g., natriuresis in a low-salt diet or other physiological stimulation) would be best suited.  Monitoring of urine and plasma electrolytes as well as heart rate and blood pressure are recommended.

Additional Information

Clinical Trials for this compound

See all of the Clinical Trials currently associated with this compound:

Publications for this compound

No publications. Access to confidential information can be made available upon request.

Gene information from the NCBi

This compound works on the following genes: