ATC code None PubChem CID 10156152 ECHA InfoCard 100.005.564 | CAS Number 302-23-8 ChemSpider 8331660 Molar mass 372.498 g/mol | |
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Synonyms Hydroxyprogesterone acetate, acetoxyprogesterone, 17α-acetoxyprogesterone | ||
Hydroxyprogesterone acetate (OHPA) (INN) (brand name Prodox), or 17α-hydroxyprogesterone acetate, also known as 17α-acetoxyprogesterone or simply acetoxyprogesterone, is an orally active steroidal progestin related to hydroxyprogesterone caproate (OHPC) which was discovered in 1953 and was first marketed by Upjohn in the United States in 1957. It is a derivative of progesterone and the acetate ester of 17α-hydroxyprogesterone, as well as the parent compound of a number of progestins including chlormadinone acetate, cyproterone acetate, medroxyprogesterone acetate, and megestrol acetate.
Contents
Pharmacology
OHPA is a progestogen and acts as an agonist of the progesterone receptor (PR), both PRA and PRB isoforms (IC50 = 16.8 nM and 12.6 nM, respectively). It has far (>50-fold) higher affinity for the PR isoforms than 17α-hydroxyprogesterone, a little less than half the affinity of progesterone, and slightly higher affinity than OHPC.
OHPA is of relatively low potency as a progestogen, which may explain its limited relative use. It is 100-fold less potent than medroxyprogesterone acetate, 400-fold less potent than chlormadinone acetate, and 1200-fold less potent than cyproterone acetate in animal assays. In terms of producing full progestogenic changes on the endometrium in women, 75 to 100 mg/day oral OHPA is equivalent to 20 mg/day parenteral progesterone, and OHPA is at least twice as potent as oral ethisterone in such regards. OHPA also is reportedly more potent than OHPC.
History
In 1949, it was discovered that 17α-methylprogesterone had twice the progestogenic activity of progesterone when administered parenterally, and this finding led to renewed interest in 17α-substituted derivatives of progesterone as potential progestins. Along with OHPC, OHPA was synthesized by Karl Junkmann of Schering AG in 1953 and was first reported by him in the medical literature in 1954. OHPC shows very low oral activity and was introduced for use via intramuscular injection by Squibb in 1956 under the brand name Delalutin. Although a substantial prolongation of action occurs when OHPC is formulated in oil, the same was not observed to a significant extent with OHPA, and this is likely why OHPC was chosen by Schering for development over OHPA.
Subsequently, Upjohn unexpectedly discovered that OHPA, unlike OHPC and progesterone, is orally active and shows marked progestogenic activity with oral administration, a finding that had been missed by the Schering researchers (who were primarily interested in the oil solubility of such esters). OHPA was found to possess two to three times the oral activity of 17α-methylprogesterone. Upjohn reported the oral activity of OHPA in the medical literature in 1957 and introduced the drug for medical use as Prodox in 25 mg and 50 mg oral tablet formulations later the same year. OHPA was indicated for the treatment of a variety of gynecological disorders in women, including secondary amenorrhea, functional uterine bleeding, infertility, habitual abortion, dysmenorrhea, and premenstrual syndrome. However, it saw relatively little use, which was perhaps due its comparatively low potency relative to a variety of other progestins such as medroxyprogesterone acetate and norethisterone that were introduced around the same time and hence that may have been favored.
In 1960, OHPA was introduced as Prodox as an oral progestin for veterinary use for the indication of estrus suppression in dogs. However, probably due its high cost and the inconvenience of daily oral administration, the drug was not a market success. It was superseded for this indication by medroxyprogesterone acetate (brand name Promone) in 1963, which could be administered by injection conveniently once every six months, although this preparation was discontinued in 1966 for various reasons and hence was not a market success either.