TABLE B12.1 Antiprogestational and Antiglucocorticoid Activities of RU 486, ZK 98 734, and ZK 98 299

Parameter

RU 486

ZK 98 734

ZK 98 299

Relative binding affinity (R 5020 = 100%) for progesterone-receptors using rabbit uterine cytosol (%)

68

72

19

Antiglucocorticoid activity (%)a

100

4

5

Abortifacient activity

 

 

 

Rats (days 5–7 post coitum)

 

 

 

3 mg/day

4/4b

4/4

4/4

1 mg/day

2/4

4/4

4/4

0.3 mg/day

0/4

1/4

0/4

Guinea pigs (days 43-44 post coitum)

 

 

 

30 mg/day

4/9

6/6

7/9

10 mg/day

3/9

5/7

5/9

1 mg/day

1/7

5/8

0/9

a Based upon reversal of dexamethasone-induced tyrosine aminotransferase activity in cultured rat hepatoma cells.

b The abortion figures indicate the number of animals aborting versus the number of animals treated. Compounds were administered by the subcutaneous route in an oil base once daily on days 5–7 post coitum in rats and on days 43– 44 in guinea pigs.

SOURCE: Based on Puri and Van Look (1991).

devoid of antiglucocorticoid activity are almost a sine qua non if they are going to be used for long periods of time, such as in the treatment of breast cancer or endometriosis, or as a daily contraceptive pill. On the other hand, pure antiglucocorticoids need to be developed that have no effect on the menstrual cycle and early pregnancy, and hence could also be used in countries where a compound with dual antiglucocorticoid and antiprogestational activities may not be made available becuase of, for example, restrictive abortion legislation. Attempts are under way to produce more selective molecules by using information from structure-activity relationships of existing compounds (Philibert et al., 1989) and from computer modeling studies of the stereochemical complementarity of steroid hormones and cavities between base pairs in DNA (Hendry and Mahesh, 1992).

ANIMAL MODELS

Identification of potential antiprogestogens generally involves, in the first instance, determination of the in vitro binding affinities of the newly synthesized compounds for the progesterone receptor and receptors of other steroid hormones. Compounds showing high binding affinity for the progesterone receptor are then assessed in appropriate animal models to determine if they are agonists or antagonists. The models used for this purpose and for evaluating the full hormonal and



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