Target Validation Information
Target ID T22939
Target Name Progesterone receptor
Target Type
Successful
Drug Potency against Target Ethynodiol Diacetate Drug Info EC50 = 208 nM [552806]
ONAPRISTONE Drug Info Ki = 18 nM [534695]
4-(2,4-diethyl-1H-pyrrol-3-yloxy)benzonitrile Drug Info IC50 = 224 nM [530880]
PF-02367982 Drug Info IC50 = 47 nM [530880]
Desogestrel Drug Info IC50 = 55200 nM [552868]
1-Benzyl-3-phenylquinazoline-2,4(1H,3H)-dione Drug Info IC50 = 11000 nM [529568]
2-(4-Amino-3'-chloro-biphenyl-3-yl)-propan-2-ol Drug Info IC50 = 103 nM [526276]
3,3-dimethyl-5-m-tolyl-2,3-dihydro-1H-inden-1-one Drug Info IC50 = 225 nM [530484]
WAY-255348 Drug Info IC50 = 4.1 nM [529352]
2,2,4-Trimethyl-6-phenyl-1,2-dihydro-quinoline Drug Info Ki = 133 nM [534695]
3-Phenyl-1-propylquinazoline-2,4(1H,3H)-dione Drug Info IC50 = 18000 nM [529568]
LGD-5552 Drug Info Ki = 866 nM [529166]
Norethindrone Drug Info EC50 = 30 nM [552377]
Norethindrone Drug Info EC50 = 1.2 nM [552806]
Norethindrone Drug Info EC50 = 0.12 nM [553215]
AL-43 Drug Info Ki = 1790 nM [526567]
Megestrol Drug Info EC50 = 4.8 nM [552806]
Lecanindole D Drug Info IC50 = 5.5 nM [530483]
3-(3,3-dimethyl-2-oxoindolin-5-yl)benzonitrile Drug Info IC50 = 27 nM [529352]
5-(2-oxoindolin-5-yl)-1H-pyrrole-2-carbonitrile Drug Info IC50 = 300 nM [529352]
6-(3-Nitro-phenyl)-3H-benzothiazol-2-one Drug Info IC50 = 84 nM [527672]
Action against Disease Model Norethindrone The progestin-specific stimulation of alkaline phosphatase (AP) activity in cells of the T47D h uMan breast cancer line was applied to the development of a sensitive microtiter plate bioassay for the quantitative evaluation of progestagenic and antiprogestagenic potencies of natural and synthetic compounds. Some of the steroids tested (viz. progesterone, medroxyprogesterone acetate, norethynodrel) behaved as full-agonists, capable of inducing AP activities to the same maximal levels (equal efficacy), while others (norethindrone, gestrinone, R5020, norgestrel, Org OD 14 and its 4-ene metabolite) behaved as partial agonists, eliciting lower maximal effects. Efficacy, EC50 values (concentrations at which they induce one-half of the maximal response) and "slope factors" serve to characterize agonistic effects. Relative progestagenic potencies among the full-agonists were evaluated by comparing EC50 concentrations. Several 19-nor synthetic progestins (norethynodrel, norethindrone, Org OD 14 and its 4-ene isomer, dl-norgestrel, levo-norgestrel, RU2323), but none of the tested progestins with the pregnane structure, showed intrinsic estrogenic activity, as evaluatedby using a similar in vitro bioassay based on a previously reported estrogen-specific induction of AP in h uMan endometrial adenocarcinoma cells of the Ishikawa Var-1 line. Maximal estrogenic effectsof all the tested progestins with dual activity were as high as those of estradiol. However, these compounds widely varied in their EC50 values for estrogenic activity. Consequently, the in vitro bioassays can reveal differences in the ratio of progestagenic and estrogenic activities intrinsic to these compounds. The reduced capability of the partial agonists to exert progestagenic or estrogenic effects on AP expression may reflect an impeded, receptor-mediated action, a mechanism that would also account for their inhibitory effects on the induction of AP activity by full agonists. Partial progestagenic agonists were able to reduce the efficacy of a full agonist to their own partial maximal activity. [553215] Drug Info
Medroxyprogesterone The progestin-specific stimulation of alkaline phosphatase (AP) activity in cells of the T47D h uMan breast cancer line was applied to the development of a sensitive microtiter plate bioassay for the quantitative evaluation of progestagenic and antiprogestagenic potencies of natural and synthetic compounds. Some of the steroids tested (viz. progesterone, medroxyprogesterone acetate, norethynodrel) behaved as full-agonists, capable of inducing AP activities to the same maximal levels (equal efficacy), while others (norethindrone, gestrinone, R5020, norgestrel, Org OD 14 and its 4-ene metabolite) behaved as partial agonists, eliciting lower maximal effects. Efficacy, EC50 values (concentrations at which they induce one-half of the maximal response) and "slope factors" serve to characterize agonistic effects. Relative progestagenic potencies among the full-agonists were evaluated by comparing EC50 concentrations. Several 19-nor synthetic progestins (norethynodrel, norethindrone, Org OD 14 and its 4-ene isomer, dl-norgestrel, levo-norgestrel, RU2323), but none of the tested progestins with the pregnane structure, showed intrinsic estrogenic activity, as evaluatedby using a similar in vitro bioassay based on a previously reported estrogen-specific induction of AP in h uMan endometrial adenocarcinoma cells of the Ishikawa Var-1 line. Maximal estrogenic effectsof all the tested progestins with dual activity were as high as those of estradiol. However, these compounds widely varied in their EC50 values for estrogenic activity. Consequently, the in vitro bioassays can reveal differences in the ratio of progestagenic and estrogenic activities intrinsic to these compounds. The reduced capability of the partial agonists to exert progestagenic or estrogenic effects on AP expression may reflect an impeded, receptor-mediated action, a mechanism that would also account for their inhibitory effects on the induction of AP activity by full agonists. Partial progestagenic agonists were able to reduce the efficacy of a full agonist to their own partial maximal activity. [553215] Drug Info
Norgestimate Specific cognitive abilities and motor function were investigated at 5.5 years in 104 children with epileptic mothers and in 105 control children, all with normal general intelligence. The majority (89 per cent) of the children of epileptic mothers had been exposed to anti-epileptic drugs during pregnancy, most commonly phenytoin (69 per cent). Maternal seizures had occurredduring pregnancy in 52 per cent. A significant difference, with poorer performance in the study group, was found in block design (WPPSI) and auditory closure (ITPA). Significantly more study than control children had some type of specific cognitive dysfunction. Within the study group, increased risk was associated with maternal partial seizures, with seizures occurring during pregnancy, and with low paternal education, but not with exposure to anti-epileptic drugs. Three possible mechanisms of this effect are suggested: subtle brain-damage associated with fetal asphyxia during the mothers' generalized convulsions; genetically transmitted brain abnormalities; and psychosocial disadvantage limiting partner choice.IC50: 0.02 nM [553083] Drug Info
References
Ref 552806Structure-activity relationships of synthetic progestins in a yeast-based in vitro androgen bioassay. J Steroid Biochem Mol Biol. 2008 May;110(1-2):39-47. doi: 10.1016/j.jsbmb.2007.10.008. Epub 2008 Feb 12.
Ref 553215Estrogenic and progestagenic activities coexisting in steroidal drugs: quantitative evaluation by in vitro bioassays with human cells. J Steroid Biochem Mol Biol. 1994 Jan;48(1):89-94.
Ref 534695J Med Chem. 1998 Aug 27;41(18):3461-6.Discovery and preliminary SAR studies of a novel, nonsteroidal progesterone receptor antagonist pharmacophore.
Ref 530880Bioorg Med Chem Lett. 2010 Jun 1;20(11):3384-6. Epub 2010 Apr 13.Optimisation of a pyrazole series of progesterone antagonists; Part 1.
Ref 530880Bioorg Med Chem Lett. 2010 Jun 1;20(11):3384-6. Epub 2010 Apr 13.Optimisation of a pyrazole series of progesterone antagonists; Part 1.
Ref 553215Estrogenic and progestagenic activities coexisting in steroidal drugs: quantitative evaluation by in vitro bioassays with human cells. J Steroid Biochem Mol Biol. 1994 Jan;48(1):89-94.
Ref 552868In vitro inhibition of CYP1A2 by model inhibitors, anti-inflammatory analgesics and female sex steroids: predictability of in vivo interactions. Basic Clin Pharmacol Toxicol. 2008 Aug;103(2):157-65. doi: 10.1111/j.1742-7843.2008.00252.x.
Ref 529568Bioorg Med Chem. 2008 Jul 15;16(14):7046-54. Epub 2008 May 10.Progesterone receptor antagonists with a 3-phenylquinazoline-2,4-dione/2-phenylisoquinoline-1,3-dione skeleton.
Ref 526276Bioorg Med Chem Lett. 2002 Mar 11;12(5):787-90.Potent nonsteroidal progesterone receptor agonists: synthesis and SAR study of 6-aryl benzoxazines.
Ref 530484Bioorg Med Chem Lett. 2009 Dec 1;19(23):6666-9. Epub 2009 Oct 7.5-Aryl indanones and derivatives as non-steroidal progesterone receptor modulators.
Ref 529352J Med Chem. 2008 Mar 27;51(6):1861-73. Epub 2008 Mar 5.Design, synthesis, and SAR of new pyrrole-oxindole progesterone receptor modulators leading to 5-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile (WAY-255348).
Ref 534695J Med Chem. 1998 Aug 27;41(18):3461-6.Discovery and preliminary SAR studies of a novel, nonsteroidal progesterone receptor antagonist pharmacophore.
Ref 529568Bioorg Med Chem. 2008 Jul 15;16(14):7046-54. Epub 2008 May 10.Progesterone receptor antagonists with a 3-phenylquinazoline-2,4-dione/2-phenylisoquinoline-1,3-dione skeleton.
Ref 529166Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19244-9. Epub 2007 Nov 21.Antiinflammatory glucocorticoid receptor ligand with reduced side effects exhibits an altered protein-protein interaction profile.
Ref 553083Specific cognitive dysfunction in children with epileptic mothers. Dev Med Child Neurol. 1990 May;32(5):403-14.
Ref 552377Estrogenic potential of progestins in oral contraceptives to stimulate human breast cancer cell proliferation. Cancer Res. 1992 Dec 1;52(23):6539-46.
Ref 552806Structure-activity relationships of synthetic progestins in a yeast-based in vitro androgen bioassay. J Steroid Biochem Mol Biol. 2008 May;110(1-2):39-47. doi: 10.1016/j.jsbmb.2007.10.008. Epub 2008 Feb 12.
Ref 553215Estrogenic and progestagenic activities coexisting in steroidal drugs: quantitative evaluation by in vitro bioassays with human cells. J Steroid Biochem Mol Biol. 1994 Jan;48(1):89-94.
Ref 526567J Med Chem. 2003 Mar 13;46(6):1016-30.Nonsteroidal selective glucocorticoid modulators: the effect of C-10 substitution on receptor selectivity and functional potency of 5-allyl-2,5-dihydro-2,2,4-trimethyl-1H-[1]benzopyrano[3,4-f]quinolines.
Ref 552806Structure-activity relationships of synthetic progestins in a yeast-based in vitro androgen bioassay. J Steroid Biochem Mol Biol. 2008 May;110(1-2):39-47. doi: 10.1016/j.jsbmb.2007.10.008. Epub 2008 Feb 12.
Ref 530483J Nat Prod. 2009 Nov;72(11):1944-8.The lecanindoles, nonsteroidal progestins from the terrestrial fungus Verticillium lecanii 6144.
Ref 529352J Med Chem. 2008 Mar 27;51(6):1861-73. Epub 2008 Mar 5.Design, synthesis, and SAR of new pyrrole-oxindole progesterone receptor modulators leading to 5-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile (WAY-255348).
Ref 529352J Med Chem. 2008 Mar 27;51(6):1861-73. Epub 2008 Mar 5.Design, synthesis, and SAR of new pyrrole-oxindole progesterone receptor modulators leading to 5-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile (WAY-255348).
Ref 527672J Med Chem. 2005 Aug 11;48(16):5092-5.Synthesis and structure-activity relationship of novel 6-aryl-1,4-dihydrobenzo[d][1,3]oxazine-2-thiones as progesterone receptor modulators leading to the potentand selective nonsteroidal progesterone receptor agonist tanaproget.

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