Spirorenone (

INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway. Before the advent of motorized transportation, they also provided accomm ...

; developmental code ZK-35973) is a

steroid A steroid is an organic compound with four fused compound, fused rings (designated A, B, C, and D) arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes t ...

antimineralocorticoid A mineralocorticoid receptor antagonist (MRA or MCRA) or aldosterone antagonist, is a diuretic drug which receptor antagonist, antagonizes the action of aldosterone at mineralocorticoid receptors. This group of drugs is often used as adjunctive t ...

of the

spirolactone Spirolactones are a class of functional group in organic chemistry featuring a cyclic ester attached spiro to another ring system. The name is also used to refer to a class of synthetic steroids, called steroid-17α-spirolactones, 17α-spirol ...

group that was never marketed. Spirorenone possesses 5–8 times the antimineralocorticoid activity of

spironolactone Spironolactone, sold under the brand name Aldactone among others, is classed as a diuretic medication. It can be used to treat edema, fluid build-up due to hepatic cirrhosis, liver disease or kidney disease. It is also used to reduce risk o ...

in animal studies. The initial discovery of spirorenone was deemed a great success, as no compound with greater antimineralocorticoid activity had been developed since spironolactone in 1957. Moreover, spirorenone itself has virtually no

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

for the

androgen receptor The androgen receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear receptor that is activated by binding any of the androgenic hormones, including testosterone and dihydrotestosterone, in th ...

while its

progestogen Progestogens, also sometimes written progestins, progestagens or gestagens, are a class of natural or synthetic steroid hormones that bind to and activate the progesterone receptors (PR). Progesterone is the major and most important progestoge ...

ic activity shows species differences, being somewhat greater than that of spironolactone in rabbits but absent in mice and rats. As such, it was characterized as a highly potent antimineralocorticoid with far fewer hormonal side effects relative to spironolactone. In

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

s, spirorenone was found to be 4- to 10-fold as potent as spironolactone as an antimineralocorticoid, and is said to be the most active antimineralocorticoid identified to date. However, it was serendipitously and unexpectedly found that low doses of spirorenone lowered

testosterone Testosterone is the primary male sex hormone and androgen in Male, males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testicles and prostate, as well as promoting se ...

levels in men during clinical studies. This was determined to be due to

metabolic conversion Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

of spirorenone into

drospirenone Drospirenone is a progestin and antiandrogen medication which is used in birth control pills to prevent pregnancy and in menopausal hormone therapy, among other uses. It is available both alone under the brand name Slynd and in combination ...

(1,2-dihydrospirorenone) by the

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

Δ¹-hydrase, a transformation that occurs only in monkeys and humans. Unlike spirorenone, drospirenone was found to be a highly potent

progestin A progestogen, also referred to as a progestagen, gestagen, or gestogen, is a type of medication which produces effects similar to those of the natural female sex hormone progesterone in the body. A progestin is a '' synthetic'' progestogen. ...

and

antiandrogen Antiandrogens, also known as androgen antagonists or testosterone blockers, are a class of drugs that prevent androgens like testosterone and dihydrotestosterone (DHT) from mediating their biological effects in the body. They act by blocking t ...

in addition to antimineralocorticoid, with 8-fold the potency of spironolactone as an antimineralocorticoid and 0.3 times the potency of

cyproterone acetate Cyproterone acetate (CPA), sold alone under the brand name Androcur or Ethinylestradiol/cyproterone acetate, with ethinylestradiol under the brand names Diane or Diane-35 among others, is an antiandrogen and progestin medication used in the tre ...

as an antiandrogen. Subsequently, investigation of spirorenone was discontinued and drospirenone was developed and eventually introduced instead as a

contraceptive Birth control, also known as contraception, anticonception, and fertility control, is the use of methods or devices to prevent pregnancy. Birth control has been used since ancient times, but effective and safe methods of birth control only be ...

Synthesis

The 7-hydroxylation of 15,16β-cyclopropan-Androstenolone PC13075949 (1). Though this transformation has also been accomplished by chemical means, microbiological oxidation by Botryodiplodia malorum apparently proves superior to give PC44520204 (2). Acylation with pivalic anhydride proceeds selectively at the 3 hydroxyl group 2543-09-7(). Epoxidation by means of tertiary butylhydroperoxide (tbhp) and Vanadyl acetylacetonate gives affords exclusively the β-epoxide 2544-13-6(3). The remaining hydroxyl is then displaced by chlorine by means of triphenylphosphine and carbon tetrachloride, PC13075960 (4). Sequential reductive elimination followed by saponification gives the allylic alcohol 2543-15-5(5). Reaction with the Simmons-Smith reagent affords the corresponding cyclopropane 2543-16-6(6) the stereochemistry being determined by the adjacent hydroxyl group. Addition of the dianion from propargyl alcohol to the carbonyl group at position 17 adds the required carbon atoms for the future lactone 2543-17-7(7). The alkyne bond is doubly reduced by catalytic hydrogenation 2543-18-8(8). Pyridinium chlorochromate (PCC) mediated oxidation converts the primary alcohol to an acid while the secondary C3 alcohol is oxidized to a oxidized to a β-hydroxyketone (9). The carboxylic acid lactonizes to the gbl ring, while dehydration of the 5β-hydroxyl group leads to the conjugated enone (10). Dehydrogenation by means of DDQ introduces the C1=C2 olefin to afford spirorenone.

References

{{Progesterone receptor modulators Antimineralocorticoids Cyclopropanes Pregnanes Progestogens Spiro compounds Spirolactones Steroidal antiandrogens

Synthesis

See also

References