Novel 6-aryl-1,4-dihydrobenzo[d]oxazine-2-thiones as potent, selective, and orally active nonsteroidal progesterone receptor agonists.

Article Details

Citation

Zhang P, Terefenko EA, Fensome A, Wrobel J, Winneker R, Zhang Z

Novel 6-aryl-1,4-dihydrobenzo[d]oxazine-2-thiones as potent, selective, and orally active nonsteroidal progesterone receptor agonists.

Bioorg Med Chem Lett. 2003 Apr 7;13(7):1313-6.

PubMed ID
12657271 [ View in PubMed
]
Abstract

The functional activity of 6-aryl benzoxazinone-based progesterone (PR) antagonists changed to PR agonism when the 2-carbonyl group was replaced by a 2-thiocarbonyl moiety. Based on this finding novel 6-aryl benzoxazine-2-thiones were synthesized and evaluated as PR agonists in various in vitro and in vivo assays. Several analogues had sub-nanomolar in vitro potency and showed excellent oral activities in rats. Compounds 15 and 29 had similar potencies to medroxyprogesterone acetate (MPA) in the in vitro T47D alkaline phosphatase assay and in vivo rat decidualization model. In contrast to MPA, 29 was highly selective (>500-fold) for PR over glucocorticoid and androgen receptors.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
Medroxyprogesterone acetateProgesterone receptorEC 50 (nM)0.12N/AN/ADetails
Medroxyprogesterone acetateProgesterone receptorEC 50 (nM)0.1N/AN/ADetails
Medroxyprogesterone acetateProgesterone receptorIC 50 (nM)10.8N/AN/ADetails
ProgesteroneGlucocorticoid receptorIC 50 (nM)>1000N/AN/ADetails
ProgesteroneProgesterone receptorEC 50 (nM)0.92N/AN/ADetails
ProgesteroneProgesterone receptorEC 50 (nM)0.9N/AN/ADetails