Mechanism of action: 11-beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor

Preclinical pharmacology

AZD4017 is a competitive, fully reversible inhibitor of human recombinant 11β-HSD1 (IC50 of 2 nM) and of 11β-HSD1 activity in isolated human adipocytes (1.8 nM) with cortisone as substrate. It is selective (>2000x) over human recombinant 11β-HSD2 and other closely homologous enzymes in vitro. AZD4017 has limited activity in pre-clinical species other than the cynomolgus monkey. However, related tool compounds with activity in all species are available; e.g., in diet-induced obese mice, a rodent-active AZ 11β-HSD1 inhibitor induced significant, and approximately half-maximal, reduction in adipose mass and weight gain when compound exposure was ~1 x IC50.

Safety and tolerability

In single ascending dose studies, Caucasian and Japanese volunteers were exposed to AZD4017 dosed up to 750mg BID. In a MAD study, volunteers received single doses of AZD4017 followed by repeated doses ranging from 75mg QD up to 900mg BID for 9 days. A few subjects on treatment had transient increased liver enzyme levels above ULN (>3 x ULN in one subject) with no concurrent increase in bilirubin. An activation of the HPA axis was demonstrated by an increase in ACTH and DHEAs levels and by an increase of total urinary glucocorticoid metabolites. However, s-cortisol and testosterone levels were not changed. In a Phase 2a glaucoma study, a number of subjects had incidences of raised liver enzymes at 1 x ULN, but with no associated adverse events.

Preclinical toxicity studies of up to 3 month duration have been performed in rat and non human primate. Changes in adrenal glands were noted in both preclinical species but were considered an adaptive response of this organ to altered function. Findings in the liver and the thyroid gland of rat were also considered adaptive and not degenerative in nature.

Clinical pharmacology

In a 9-day proof of mechanism study, AZD4017 (1200mg QD) significantly inhibited hepatic 11β-HSD1 activity as measured by an oral prednisone challenge. Measurements of urine glucocorticoid metabolites further indicate an inhibitory effect on the whole body 11β-HSD1 activity. Regarding the 11β-HSD1 inhibitory effect in adipose tissue, a MAD and PoM study in abdominally obese subjects demonstrated inhibition of 11β-HSD1 after single dosing, yet no sustained inhibitory effect after repeated doses at the tested dose levels. However, ex vivo investigations suggest the possibility to obtain an inhibition after repeated dosing at high AZD4017 concentrations. In a 28 day Phase 2a study in patients with raised intraocular pressure, AZD4017 dosed at 400mg BID, produced no change in IOP when compared to placebo (plasma concentrations of ~10 x IC50).

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 safety studies support future clinical studies of up to 3 month duration with the need for monitoring liver enzymes, thyroid, and adrenal function.

Additional Information

Clinical trials for this compound

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Publications for this compound

Find out more about this compound by reading related publications:

Discovery of a potent, selective, and orally bioavailable acidic 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor: discovery of 2-[(3S)-1-[5-(cyclohexylcarbamoyl)-6-propylsulfanylpyridin-2-yl]-3-piperidyl]acetic acid

Gene information from the NCBi

This compound works on the following genes: