Androgenic and anti-androgenic activities of 3-and 3,5-oxygenated a-nortestosterone derivatives

215

ANDROGENIC AND ANTI-ANDROGENIC ACTIVITIES OF 3-AND 3,5-OXYGENATED A-NORTESTOSTERONE DERIVATIVES Leonard

Albert

J. Lerner,

with

the technical Squibb

Received

June

V. Bianchi

assistance

and Margaret

Dzelzkalns

of Erna Dzelzkalns

Institute for Medical Research New Brunswick, New Jersey

1, 1965

ABSTRACT The introduction of oxygenated substituents at C3 and C5 in A-nortestosterone yields compounds which are weakly androgenic and anti-androgenic in the immature castrate male rat and the chick comb assays. Several of these compounds are more potent androgen antagonists, but are weaker androgens than A-nortestosterone. INTRODUCTION Compounds androgen

could

the research have

which

be useful

biologist.

intensified

agents

agents

estrogens

have

one testing active several little

their

of diverse

hormonal

are antagonistic

A number synthesis

system,

and testing

of these

modifications

or no hormonal (1,2,3).

have

activity

been

therefore,

Since

androgens, activity

and

in at least

and assayed.

Indeed,

shown to possess

and yet were

One class

as to

of these hormonally

been prepared

compounds

of

of chemical

for this activity.

anti-androgenic

have

as well

of laboratories,

such as progestogens,

compounds

antagonistic

to the clinician

structures

shown

to the actions

androgen

of compounds,

the A-nor-

STEROIDS

216

steroids, Most

has

yielded

prominent

(1,4) .

of inherent

androgenic

A-norsteroid

compound

is a very weak

androgen.

The present

of which

derivatives were

reported

compound

animal

hormonal

anti-androgens.

of this was

systems

action

androgen

(1).

study

but does

is concerned

activities

series

and yet,

Another

anti-

(2,4).

This

antagonize with

the andro-

of several

of A-nortestosterone

the

by Levine

(7).

MATERIALS

is

found to be

(1,5,6)

is A-nortestosterone

and anti-androgenic

oxygenated

studied

This

in several

was devoid

genie

of active

and most widely

A-norprogesterone anti-androgenic

a number

6:2

and Diassi

3-and

3,5-

syntheses

AND METHODS

Androgenic and anti-androgenic activities of SQ 17303 d-A -norandrostene-2-one-3,17B_diol A3-A-norandrostene-2-one-3,17p-diol-diacetate SQ 17399 SQ 17416 A-norandrostane-2-one-3P,58 ,17p-trio1 SQ 17447 3-Methoxy- A3 -A-norandrostene-2-one-17p-ol were assessed by the use of the chick and rat assays. Immature male Sprague-Dawley strain rats weighing 55-65 grams were castrated and randomly divided into groups of The compounds were dissolved or suspended in 4 animals. sesame oil and administered in a daily volume of 0.1 ml. Each test compound was administered alone or concomitantly with testosterone propionate (TP) at separate injection Treatment was subcutaneous once daily for 7 days sites. On the day following the starting the day of castration. last injection, the animals were sacrificed and ventral prostates and seminal vesicles were removed and weighed. Two-day old white Leghorn cockerels were employed in local comb androgen (8) and local comb anti-androgen (9) The birds were randomly distributed 5 per cage assays. and 10 per dose group and fed a standard chick starter A-norsteroids and mash with water provided -ad libitum. testosterone (T) were each dissolved or suspended in sesame oil and applied in 0.005 ml. volumes to the chick

STEROIDS

Aug. 1965

217

In the anti-androgen assay the androgen was applied comb. to one side and the test compound to the other side of Treatment was for 7 days and on the day following the comb. the last application of steroid, the chicks were sacrificed, the comb and body weights were taken, and the comb to body weight ratios calculated. RESULTS None weight

of the A-norsteroids

of rat seminal

vesicles

test dosage

with

slight,

significant,

but

weight

Surprisingly

SQ 17447 did

increase

cantly

inhibited

hypertrophy effect

latter

of chicks,

of the androgen

significantly

did

and

(Table 2).

ventral

(SQ 17383,

signifi-

prostate

prevented

of the seminal SQ 17447

the effect

a

prostate

but SQ 17399

significantly

decreased

caused

and SQ 17416)

on the weight

at the

compound

minimally

(SQ 17383

also

All of the compounds tested

this

testosterone-induced

and SQ 17416

which

of the ventral

comb weights

Two of the compounds

in the

prostates

of SQ 17383,

elevation

the comb weights

an increase

or ventral

the exception

(Table 1).

not alter

induced

the vesicle.

and SQ 17399)

of testosterone

on comb growth. DISCUSSION These assaying

results

androgenic

discriminating It should

illustrate

the chick

and anti-androgenic

than the male

be remembered

the steroids

that

are applied

activity

rat accessory

however, directly

that

comb method is less

sex organ

in the chick

to the target:

for

method.

assay

tissue,

1000 1000 + 25

1000 1000 + 25

1000 1000 i- 25

4 4

4 4

4 4

SQ 17399 SQ 17399 + TP

SQ i7416 SQ 17416 + TP

sy 17447 SQ I7447 -t TP

12.2 + 0.7 66.7 2 7.-I*

12.8 + 1.2 59.9 + 7.1 (P < -05)

15.5 _t 1.4 66.5 2 4.9*

.-Anti-androgerric activity not significant ** - Standard error of the mean TP - Testosterone propionate

*

1000 + 25

4

SQ 1.7383 + TP

a

29

a

32

10.9 f: 0.5

+ 1.5 (P < .05) 57.9 2 4.1 (P < -01)

1oocl

4

SQ 17383

19.8

44.8 t; 2.7

78.2 + 2.2

25

1.2

TP

8.9" 0.7 37.6 -+ 2.a*

9.2 + 0.7 33.9 f: 3.2

9.9 _t 0.6 40.6 2 5.2*

38.9 f 4,6*

10.6 -+ 0.4**

14.6 f l-l.**

L2

Seminal Vesicles (SV) mq

Control

% Decrease of TP-Induced VP Hypertrophy

PI

Ventral Prostate (VP) mq

ACTIVITIES OF 3-AND 3,5-OXYGENATED DERIVATIVES IN THE IMMATURE CASTRATE MALE RAT

1

Treatment l_ll

Dai1.y Dose mcq

ANI)Ro(;EEIc! AND ANTI-ANDROGSNIC

TABLE

21

32

12

17

% Decrease of TP-Induced SV Hypertrophy

OF A-NORTESTOSTERONE

0

0

0

ca l/1000

1

Androgenic Potency TP = 1

10

SQ 17447 + T

1000

50

* - P ' -01 ** - Standard error of the mean T - Testosterone

2

.05*

.06*

supply

1.08 _ir.03*

0.43 +

0.95

due to limited

1000 c 50

SQ 17416 was not tested

10

SQ 17447

f

10

SQ

1000

1000

10

SQ 17399

+ T

.04*

0.45 2

1000 + 50

10

SQ 17383 + T

17399

.06*

0.86 2

1000

10

SQ 17383

0.35 _t .06

1.24 _t .07*

50

30

T

.Of**

0.32 +

-

30

Control

Treatment

2

-.-

20

32

41

34

-

ca l/500

ca l/500

0

0

41

1

288

AND ANTI-ANDROGENIC ACTIVITIES OF 3-AND 3,5-OXYGENATED DERIVATIVES OF A-NORT~STOSTERONE ON THE'CHICK COMB % Decrease of % Increase of Total Induced chick Comb Androgenic TDose Comb Wt. (mq) Potency Chick Comb Growth Over N ~-I__~-_-_.__,IF1-*_-_-.~----._-__." Body Wt. (gm) T=l me9 Growth Control

ANDROGENIC

TABLE

STEROIDS

220

whereas

in the rat assay,

systemically changes

Generally, androgenic

prior

steroids

exceptions

study

Since

there

human

with

androgen

impossible

to choose

as the better

either system

derivatives

weaker

similar

correlation

inhibition

of the effect

androgen

(testosterone

The most

potent

(2). potent

or testosterone

of the compounds,

testosterone

propionate

the effect

of the androgen

data

It is therefore or avian in man.

that these

3-

are

and anti-androgenic These

compounds

antagonists

of androgen

standard

propionate)

SQ 17383,

achieved.

at a 4O:l

in the rat prevented

on the ventral

are

complete

of the administered

ratio with

of human

efficacy

In no case was

is A-nortestosterone.

employed.

of A-nortestosterone

in androgenic

but are more

in the

in the

assay

demonstrates

to A-nortestosterone

androgens,

experience

for predicting

3,5-oxygenated

In the

androgenic

the mammalian

investigation

activities

in the chick;

is not possible.

This present

qualitatively

than

data

tissues.

or anti-

at the doses

too little

antagonists,

assay

the reacting

rule are found.

in the chick

is at present

to metabolic

are androgenic

SQ 17383 was very weakly

and rat or chick

and

which

are administered

subject

to reaching

to this

rat, but non-androgenic

assay

are more

in the rat are also active

occasionally present

the steroids

and therefore,

and dilution

6:2

prostate

by

Aug.

STEROIDS

1965

approximately administered

30%.

in the chick,

at a 2O:l ratio with

the anticipated would

Similarly,

comb growth

be of value

of the A-norsteroid

221

this

testosterone

by approximately

to determine

whether

prevented 40%.

reasonable

are anti-androgenic

compound

It doses

in man.

REFERENCES 1.

Lerner, L. J., Bianchi, A. and Borman, EXP. BIOL. AND MED., 103, 172 (1960).

2.

Lerner, L. J., Bianchi, A., Dzelzkalns, M. and Borman, PROC. SOC. EXP. BIOL. AND MED., 115, 924 (1964).

3.

Segaloff,

4.

Weisenborn, F. L. and Applegate, sot., 81, 1960 (1959).

5.

Lerner, L. J. 434 (1964).

6.

Dorfman, R. I. PROC. (1962).

7.

Levine, S. D. and Diassi, (1965).

8.

Lerner, L. J. and Bianchi, (1963) .

9.

Lerner, L. J., Bianchi, A. and Dzelzkalns, ENDOCRINOL., 44, 398 (1963).

A. and Gabbard,

RECENT

R. B.

PROGRESS

SOC. EXP.

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A.

STEROIDS, H. E.

4, 433

RESEARCH,

AND MED.,

J. ORG. CHEM.,

A. ACTA

SOC.

ENDOCRINOL.,

M.

20,

111, 441

30,1325

44, 389

ACTA

A.

(1964).

J. AM. CHEM.

IN HORMONE

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