Potent nonsteroidal progesterone receptor agonists: Synthesis and SAR study of 6-aryl benzoxazines

Zhang, Puwen; Terefenko, Eugene A.; Fensome, Andrew; Zhang, Zhiming; Zhu, Yuan; Cohen, Jeffrey; Winneker, Richard C.; Wrobel, Jay; Yardley, J. P.

doi:10.1016/s0960-894x(02)00025-2

Cited by 108 publications

(59 citation statements)

References 14 publications

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“…T47D Alkaline Phosphatase Assay-The effect of TNPR and reference steroids on alkaline phosphatase activity in T47D cells was determined as described (34,35). Briefly, cells were plated in 96-well plates at 50,000 cells/well in DMEM/F12 with 10% FBS.…”

Section: Methodsmentioning

confidence: 99%

“…After centrifugation at 100,000 ϫ g for 1 h (4°C), the supernatant containing PR was collected and measured for protein concentration. 35 S-radiolabeled PR-B using a TNT T7 quick coupled transcription/translation system according to the manufacturer's protocol (Promega, Madison, WI). After the translation reaction, an aliquot (30 l) of the lysate was incubated for 10 min in the absence or presence of ligands at a final concentration of 100 nM.…”

Section: Methodsmentioning

confidence: 99%

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Molecular and Pharmacological Properties of a Potent and Selective Novel Nonsteroidal Progesterone Receptor Agonist Tanaproget

Zhang

Olland

Zhu

et al. 2005

Journal of Biological Chemistry

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Progesterone receptor (PR) agonists have several important applications in women's health, such as in oral contraception and post-menopausal hormone therapy. Currently, all PR agonists used clinically are steroids. Because of their interactions with other steroid receptors, steroid-metabolizing enzymes, or other steroid-signaling pathways, these drugs can pose significant side effects in some women. Efforts to discover novel nonsteroidal PR agonists with improved biological properties led to the discovery of tanaproget (TNPR). TNPR binds to the PR from various species with a higher relative affinity than reference steroidal progestins. In T47D cells, TNPR induces alkaline phosphatase activity with an EC 50 value of 0.1 nM, comparable with potent steroidal progestins such as medroxyprogesterone acetate (MPA) and trimegestone (TMG), albeit with a reduced efficacy (ϳ60%). In a mammalian two-hybrid assay to measure PR agonist-induced interaction between steroid receptor co-activator-1 and PR, TNPR showed similar potency (EC 50 value of 0.02 nM) and efficacy to MPA and TMG. Importantly, in key animal models such as the rat ovulation inhibition assay, TNPR demonstrates full efficacy and an enhanced progestational potency (30-fold) when compared with MPA and TMG. Furthermore, TNPR has relatively weak interactions with other steroid receptors and binding proteins and little effect on cytochrome P450 metabolic pathways. Finally, the three-dimensional crystal structure of the PR ligand binding domain with TNPR has been delineated to demonstrate how this nonsteroidal ligand achieves its high binding affinity. Therefore, TNPR is a structurally novel and very selective PR agonist with an improved preclinical pharmacological profile.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Molecular and Pharmacological Properties of a Potent and Selective Novel Nonsteroidal Progesterone Receptor Agonist Tanaproget

Zhang

Olland

Zhu

et al. 2005

Journal of Biological Chemistry

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“…Dihydrobenzo/naphtho[e]-1,3-oxazines are known to exhibit a wide range of valuable pharmacological properties as antitumor [10], antibacterial [11], anti-HIV [12], and antimicrobial agents [13]. In addition, 6-arylbenzoxazines have also been examined as progesterone receptor modulators and reported as potent nonsteroidal progesterone receptor agonists [14]. On the other hand, these molecules are materially very useful for making phenol type polymers such as polybenzoxazines, offers lucrative mechanical, and electrical properties [15].…”

Section: Introductionmentioning

confidence: 99%

One‐pot three‐component synthesis of dihydrobenzo‐ and naphtho[e]‐1,3‐oxazines in water

Mathew

Nath

2009

Journal of Heterocyclic Chem

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“…1,3-Oxathianes were used as chiral sulfides in asymmetric syntheses of mono-and diaryloxiranes [189,190] and trans-cyclopropanes [191,192] and were subjected to phosphorylation to obtain phospholipid analogs [193]. 1,3-Oxazines were reported as stereoinductors in the synthesis of optically pure compounds [194][195][196][197][198], and 6-arylbenzoxazines are potent nonsteroidal progesterone receptor agonists [199].…”

Section: Scheme 59mentioning

confidence: 99%

Aliphatic aldehydes in the synthesis of carbo- and heterocycles: Part II. Synthesis of six- and seven-membered rings, bicyclic compounds, and macrocycles

Dyachenko

Karpov

2011

Russ J Org Chem

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Potent nonsteroidal progesterone receptor agonists: Synthesis and SAR study of 6-aryl benzoxazines

Cited by 108 publications

References 14 publications

Molecular and Pharmacological Properties of a Potent and Selective Novel Nonsteroidal Progesterone Receptor Agonist Tanaproget

Molecular and Pharmacological Properties of a Potent and Selective Novel Nonsteroidal Progesterone Receptor Agonist Tanaproget

One‐pot three‐component synthesis of dihydrobenzo‐ and naphtho[e]‐1,3‐oxazines in water

Aliphatic aldehydes in the synthesis of carbo- and heterocycles: Part II. Synthesis of six- and seven-membered rings, bicyclic compounds, and macrocycles

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