Preclinical pharmacological profile of nomegestrol acetate, a synthetic 19-nor-progesterone derivative

Harry A Van Diepen

doi:10.1186/1477-7827-10-85

Abstract

BackgroundNomegestrol acetate (NOMAC), a synthetic progestogen derived from 19-nor-progesterone, recently completed clinical trials for use with 17beta-estradiol in a new monophasic combined oral contraceptive. In this review, published as well as previously unpublished preclinical studies that detail the effects of NOMAC on estrogenic, progestogenic, and androgenic systems, as well as mineralocorticoid, glucocorticoid, bone, and metabolic indices are described.MethodsIn vitro assays to determine NOMAC structure-activity relationships used tissue derived from rat uteri. Transactivation profiles were performed using Chinese hamster ovary (CHO) cells transfected with cDNAs encoding human steroid receptors. Estrogenic and anti-estrogenic activities were monitored in vivo in rats as well as in vitro in human breast cancer cells. Standard in vivo techniques were used in rats to determine progestational activity; antigonadotropic, androgenic, mineralocorticoid, and glucocorticoid activities; as well as effects on bone and other metabolic indices. Ovulation inhibition was monitored in rats and primates. NOMAC’s effects on cardiovascular systems were determined in dogs and primates.ResultsNOMAC was without significant agonistic or antagonistic activity for estrogen receptor alpha or beta in vitro, and inhibited ovulation in rats and monkeys (2.5 mg/kg and 1 mg/kg, respectively). NOMAC lacked androgenic, antimineralocorticoid, glucocorticoid, and metabolic activity and exhibited moderate anti-androgenic activity in rats. NOMAC did not affect bone mineral density (BMD) in rats or hemodynamic and electrophysiologic parameters in dogs and primates.ConclusionsNOMAC is a selective progestogen structurally similar to progesterone that has modest anti-androgenic activity and does not affect lipid or carbohydrate metabolism, BMD, or many cardiovascular parameters in selected animal models.

Highlights

Nomegestrol acetate (NOMAC), a synthetic progestogen derived from 19-nor-progesterone, recently completed clinical trials for use with 17beta-estradiol in a new monophasic combined oral contraceptive
Duc et al [12] determined the apparent binding constant at equilibrium, maximum concentration of binding sites (Bmax), the dissociation rate constant k−1, and the specific relative binding affinity (RBA) of radiolabeled NOMAC to progesterone receptor (PR) derived from the uteri of estrogen-primed rats
The IC50 of dexamethasone was unchanged after 24 hours, the IC50 of NOMAC increased to 1493 ± 807 nmol/L (1%). These results demonstrate that NOMAC has less affinity for rat liver glucocorticoid receptor (GR) over time. These results suggest a low association and faster dissociation to rat GR of NOMAC compared with dexamethasone

Summary

Introduction

Nomegestrol acetate (NOMAC), a synthetic progestogen derived from 19-nor-progesterone, recently completed clinical trials for use with 17beta-estradiol in a new monophasic combined oral contraceptive. In this review, published as well as previously unpublished preclinical studies that detail the effects of NOMAC on estrogenic, progestogenic, and androgenic systems, as well as mineralocorticoid, glucocorticoid, bone, and metabolic indices are described. Most combined oral contraceptives (COCs) in use today contain a synthetic progestogen (predominantly 19nortestosterone derivatives) and a synthetic estrogen, ethinyl estradiol (EE). In the early 1980s, nomegestrol acetate (NOMAC), a progestogen derived from 19nor-progesterone, was synthesized (Figure 1) [1,2,3].

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