Progesterone analogues

Extracts of corpora lutea were known ia the early tweatieth ceatury to inhibit ovulatioa ia animals. Pure progesterone (3), the active component of the extracts, was isolated ia 1934 and its stmcture reported (15). Several problems limited its use and drove efforts to develop progesterone analogues, ie, it was available only ia small quantities from animal sources, was not orally active, and was discovered to cause androgenic side effects. 

Dydrogesterone is a progesterone analogue. One of its indications is endometriosis, in which case dydrogesterone is administered at a dose of 10 mg two to three times daily. Progestogens are contraindicated in severe liver impairment and in patients with a history of liver tumours. 

Many of the foregoing modified progesterone analogues exhibit improved biopharmaceutical properties over progesterone proper. The derivatives that follow were likely prepared in the hope that combinations of substituents would lead to additive improvements, a circumstance that often prevails in the pregnane series. 

Hydrolysis with mercuric chloride-cadmium carbonate furnished the 17 -hydroxy-ketone (192), which was converted into the homoisoprogesterone derivative (193) and dehydrated under acidic conditions to the A -homo-progesterone analogue (194). ° ... 

The structure of 4 -propyl-4/3,5/3-cthcnopregnanc-3,20-dione (131) as the main product of photochemical [2 + 2] cycloaddition of 1-pentyne to progesterone and 4a,5a-analogue 138 was confirmed by X-ray analysis. The CD data of 131-140 were in agreement with A/B-cis and AfB-trans fusion in 131 and 138, respectively, and with the cyclobutene ring (main perturber of the C=0 n —> jr transition) lying in a (—)-octant of 131 and a (+)-octant of 138323. 

Progesterone, the physiological progestogen, has long been overshadowed in medical treatment by its synthetic analogues, because of their superior oral absorption. 

Hormones and analogues growth hormone corticotrophin (ACTH) calcitonin desmopressin (DD AVP) lypressin oxytocin buserelin nafarelin progesterone norethisterone 17/1-estradiol testosterone insulin Gonadorelin (Gonadotrophin-releasing hormone GnRH LH-RH)... 

Oestrone lacks one of progesterone s methyl groups, probably removed in the body as CO2 after oxidation. In 1946, Carl Djerassi, a man whose work led directly to the invention of the contraceptive pill, showed that another derivative of cholesterol could be rearranged to the oestrone analogue 1-methyloestradiol—notice how the methyl group has this time migrated to an adjacent carbon atom. At the same time, the dienone has become a phenol. 

Unlike prednisolone and dexamethasone, which are structurally related to cortisol, fluorometholone is a fluo-rinated structural analogue of progesterone. Formulated both as an alcohol and acetate derivative, fluorometholone has proven to be an effective agent in external ocular inflammations, with relatively low potential for elevating lOP. 

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