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PubMed1989

Sex steroids and steroid binding proteins in primary biliary cirrhosis.

In a longitudinal study on sex steroids and steroid binding proteins in primary biliary cirrhosis (PBC), 9 female patients were compared with 27 strictly age-matched healthy controls. In the patients we found elevated levels of androstenedione and, in advanced disease, of testosterone. Levels of total oestrone, dehydroepiandrosterone and dehydroepiandrosterone sulphate (DHAS) were not significantly different from controls, although numerically lower values were noted for the two later steroids in the PBC patients. The mean albumin level in the PBC patients was at the lower reference limit. A significant positive correlation between DHAS and albumin was found in the patients. The levels of sex hormone binding globulin (SHBG) were elevated in the patients and increased further with progressive disease as measured by N-demethylating capacity. The results suggest a close association, unrelated to sex hormone levels, between increased SHBG synthesis and progressive hepatocellular failure in PBC.

Adult↗
PubMed1989

Human placental 3 beta-hydroxy-5-ene-steroid dehydrogenase and steroid 5----4-ene-isomerase: purification from mitochondria and kinetic profiles, biophysical characterization of the purified mitochondrial and microsomal enzymes.

In human placenta, 3 beta-hydroxy-5-ene-steroid dehydrogenase and steroid 5----4-ene-isomerase, an enzyme complex found in microsomes and mitochondria, synthesizes progesterone from pregnenolone and androstenedione from fetal dehydroepiandrosterone sulfate. The dehydrogenase and isomerase activities of the mitochondrial enzyme were copurified (733-fold) using sequential cholate solubilization, ion exchange chromatography (DEAE-Toyopearl 650S), and hydroxylapatite chromatography (Bio-Gel HT). Enzyme homogeneity was demonstrated by a single protein band in SDS-polyacrylamide gel electrophoresis (monomeric Mr = 41,000), gel filtration at constant specific enzyme activity (Mr = 77,000), and a single NH2-terminal sequence. Kinetic constants were determined for the oxidation of pregnenolone (Km = 1.6 microM, Vmax = 48.6 nmol/min/mg) and dehydroepiandrosterone (Km = 2.4 microM, Vmax = 48.5 nmol/min/mg) and for the isomerization of 5-pregnene-3,20-dione (Km = 9.3 microM, Vmax = 914.2 nmol/min/mg) and 5-androstene-3,17-dione (Km = 27.6 microM, Vmax = 888.4 nmol/min/mg. Mixed substrate studies showed that the dehydrogenase and isomerase activities utilize their respective pregnene and androstene substrates competitively. Dixon analysis demonstrated that the product steroids, progesterone and androstenedione, are competitive inhibitors of the C-21 and C-19 dehydrogenase activities. Enzyme purified from mitochondria and microsomes had similar kinetic profiles with respect to substrate utilization, product inhibition, and cofactor (NAD+) reduction (mean Km +/- SD using C-19 and C-21 dehydrogenase substrates = 26.4 +/- 0.8 microM, mean Vmax = 73.2 +/- 1.3 nmol/min/mg). Pure enzyme from both organelles exhibited identical biophysical properties in terms of molecular weight and subunit composition, pH optima (pH 9.8, dehydrogenase; pH 7.5, isomerase), temperature optimum (37 degrees C), stability in storage and solution, effects of divalent cations, and the single NH2-terminal sequence of 27 amino acids. These results suggest that the mitochondrial and microsomal enzymes are the same protein localized in different organelles.

3-Hydroxysteroid Dehydrogenases↗
PubMed1981

Steroid structural requirements for high affinity binding to human sex steroid binding protein (SBP).

The sex steroid binding protein (SBP) which binds androgens circulating in the blood of man has been examined to determine the structural requirements for high affinity binding. SBP was purified partially and the ability of each of more than 150 steroids to compete with [3H]dihydrotestosterone (17 beta-hydroxy-5 alpha-androstan-3-one) for binding to SBP was assessed. Binding was enhanced by reduction of the delta 4 double bond to 5 alpha-dihydro, addition of a methyl group at C-4 and in one case unsaturation at C-14,15. Affinity was always reduced by modifications of the C-17 beta hydroxy. Binding was also severely decreased by deletion of the keto moiety at C-3; however, relatively high affinity was retained by an alcohol or an unsubstituted pyrazole group at C-3. Certain alpha surface substitutions such as 17 alpha-ethinyl had limited effects on binding; whereas, other modifications such as 7 alpha-methyl or 17 alpha-methyl caused significant reduction in binding. Most modifications at C-2, 6, 9 or 11 also impaired affinity, and the 5 beta steroids had reduced affinity.

Androgen-Binding Protein↗
PubMed1985

Reaction of some antiinflammatory 17 beta-(2-aminooxazol-4-yl) steroids with hydrogen peroxide. Synthesis of steroid-17-spiro-5'-oxazolidine-2',4'-diones.

The heterocyclic moiety of 17 beta-(2-aminooxazol-4-yl) steroids is sensitive to the oxidizing action of hydrogen peroxide and yields products mainly from the opening of the amino-oxazole ring. Unlike simple 2-aminooxazoles, it does not rearrange to 2-imidazolone and the expected steroidal hydroperoxyimidazolidinones were not detected. Among the substances we isolated, N-(aminocarbonyl)-17 alpha-hydroxy-17-carboxamides (2a) and (3a) undergo spontaneous cyclization, in the reaction conditions, giving steroid-17-spirooxazolidinediones (2d) and (3d). Spirane (2d) was synthesized in high yields from (2a) in strongly alkaline medium.

Anti-Inflammatory Agents↗
PubMed1992

Steroids, the steroid community, and Upjohn in perspective: a profile of innovation.

The announcement in 1949 at the Mayo Clinic of the dramatic effect of cortisone in alleviating the symptoms of rheumatoid arthritis triggered a competitive worldwide research and development effort directed toward a single goal, the practical synthesis of the rare corticosteroids. The confluence of an extraordinary coalescence of multiple events and circumstances in the growth of the Upjohn Company with the Mayo discovery, inclusive of a pioneering role in the steroid field, conspired to create an environment ripe for innovation. The breakthrough, which gave Upjohn an early competitive edge, followed with startling swiftness. A common mold of the genus Rhizopus was found to introduce enzymatically an 11 alpha-hydroxyl group directly into the female hormone progesterone, which had just been synthesized from the soybean sterol stigmasterol--a one-step solution to the known multistep alternatives for 11-oxygenation. Retrospective analysis of this event in perspective with other key developments before and after at Upjohn and in the steroid community reveals a striking profile of ongoing innovation. A parallel scenario in kind was repeated at Upjohn a quarter century later. The sister soybean sterol sitosterol was radically degraded microbiologically and concurrently oxygenated in ring C to produce 9 alpha-hydroxyandrostenedione, an alternative key intermediate for corticoid synthesis. New chemical processes, highly integrated with existing processes, assured the continuation of Upjohn's leading role in steroid hormone production.

Cortisone↗
PubMed1991

Effects of steroidal and non-steroidal antiandrogens on the left atrium of the rat in vitro.

1. The effect of steroidal-cyproterone acetate (CPA, 10(-7)-10(-5) M), clormadinone acetate (CMA, 10(-7)-10(-5) M), medroxyprogesterone acetate (MPA, 10(-7)-10(-5) M) and spironolactone (SPI, 10(-7)10(-5)M) and non-steroidal-flutamide (F, 10(-7)-6 x 10(-5) M) and cimetidine (C, 10(-7)-10(-4)M) antiandrogens on contractile force of electrically stimulated left atria of the rat have been assayed. 2. CPA, CMA, MPA and F inhibit, in a dose-dependent way, the contractile force of left atria. SPI enhanced (P less than 0.01 at 10(-6) M), and cimetidine did not modify the contractile force. 3. F, but not CPA, CMA, MPA or SPI, inhibit the contractile force induced by CaCl2 (0.9-7.2 mM) on electrically stimulated left atria. 4. The inhibitory effect of CPA (10(-7)-10(-5) M) was significantly increased by atropine (10(-6) M) and diltiazen (10(-5) M), and significantly reduced by yohimbine (10(-7) M) and in reserpinized (2.5 mg/kg, 48 and 24 hr before experiments) rats. 5. Our results suggest that the negative inotropism of steroidal antiandrogens could be related to inhibition of noradrenaline release, presumably through an alpha 2 adrenergic effect. The negative inotropism produced by F is related to inhibition of calcium dependent process on left atria contraction.

Androgen Antagonists↗
PubMed1992

Corticosteroid side chain oxidations--II. Metabolism of 20-dihydro steroids and evidence for steroid acid formation by direct oxidation at C-21.

Rabbits have been injected with 4-14C-labelled progesterone, deoxycorticosterone and corticosterone and the corresponding 20 beta-3H-reduced steroids (20-dihydro steroids) in order to compare the influence of oxidation at C-20 on the excretion of steroid acids. Both 20 beta-reduced progesterone and deoxycorticosterone were extensively oxidized at C-20 and metabolized to 20-oxo-21-oic acids devoid of tritium. A small proportion of the acidic metabolites of [20 beta-3H]dihydro deoxycorticosterone retained tritium. By contrast the majority of the metabolites of [20 beta-3H]dihydro corticosterone were tritiated and [11 beta,20 beta-3H]-dihydroxy-4-pregnene-3-one-21-oic acid was identified as a major acidic metabolite. These results indicate that the presence of a 11 beta-hydroxyl in 20 beta-dihydro corticosterone inhibits oxidation at C-20 and provides evidence for the direct oxidation of this corticosteroid at C-21 in this species.

Adrenal Cortex Hormones↗
PubMed2006

C19-steroids as androgen receptor modulators: design, discovery, and structure-activity relationship of new steroidal androgen receptor antagonists.

Dehydroepiandrosterone (DHEA), the most abundant steroid in human circulating blood, is metabolized to sex hormones and other C19-steroids. Our previous collaborative study demonstrated that androst-5-ene-3beta,17beta-diol (Adiol) and androst-4-ene-3,17-dione (Adione), metabolites of DHEA, can activate androgen receptor (AR) target genes. Adiol is maintained at a high concentration in prostate cancer tissue; even after androgen deprivation therapy and its androgen activity is not inhibited by the antiandrogens currently used to treat prostate cancer patients. We have synthesized possible metabolites of DHEA and several synthetic analogues and evaluated their role in androgen receptor transactivation to identify AR modulators. Steroids with low androgenic potential in PC-3 cell lines were evaluated for anti-dihydrotestosterone (DHT) and anti-Adiol activity. We discovered three potent antiandrogens: 3beta-acetoxyandrosta-1,5-diene-17-one 17-ethylene ketal (ADEK), androsta-1,4-diene-3,17-dione 17-ethylene ketal (OAK), and 3beta-hydroxyandrosta-5,16-diene (HAD) that antagonized the effects of DHT as well as of Adiol on the growth of LNCaP cells and on the expression of prostate-specific antigen (PSA). In vivo tests of these compounds will reveal their potential as potent antiandrogens for the treatment of prostate cancer.

Androgen Receptor Antagonists↗
PubMed2006

Gonadotropin stimulation of steroid synthesis and metabolism in the Rana pipiens ovarian follicle: sequential changes in endogenous steroids during ovulation, fertilization and cleavage stages.

Steroid synthesis and metabolism have been followed in Rana pipiens ovarian follicles, denuded oocytes and eggs during ovulation, fertilization and cleavage stages (blastula formation). Under physiological conditions, gonadotropin stimulation of the fully grown follicle leads to progesterone synthesis from [(3)H]acetate as well as formation of much smaller amounts of 17alpha-hydroxyprogesterone, androstenedione, pregnanedione and pregnanediol. Progesterone levels increase during completion of the first meiotic division, but by ovulation progesterone disappears from the egg. Plasma membrane-bound progesterone is taken up into the oocyte cortical granules and is largely metabolized to 5alpha-pregnane-3alphaol,20-one and 5beta-pregnane-3alpha,17alpha,20beta-triol coincident with internalization of 60% of the oocyte surface (and >90% of bound progesterone) by the end of the hormone-dependent period. The principal steroid in the ovulated egg is 5beta-pregnane-3alpha,17alpha,20beta-triol. There is a rapid efflux of 5beta-pregnane-3alpha,17alpha,20beta-triol into the medium immediately following fertilization and residual steroid levels remain low in the developing blastula. Dissociated blastulae cells prepared from stage 9 1/2 embryos concentrate both pregnenolone and progesterone from the medium with minimal metabolism. The results indicate that the ovarian follicle has the ability to synthesize and metabolize progesterone but that this ability disappears in the ovulated egg. The progesterone metabolites formed during meiosis are largely released at fertilization.

17-alpha-Hydroxyprogesterone↗
PubMed2003

Inhibition of carbonic anhydrase II by steroidal and non-steroidal sulphamates.

Carbonic anhydrases (CAs) are expressed by many solid tumours where they may act to confer a growth advantage on malignant tissues. In this study we have examined the ability of a series of steroidal and non-steroidal sulphamates (originally developed as steroid sulphatase inhibitors) and related compounds to inhibit human CAII (hCAII) activity in vitro. Using a 96-well plate assay, oestrone-3-O-sulphamate (EMATE) and two coumarin-based sulphamate drugs (667 COUMATE and STX 118) were found to have IC(50) values of 25-59 nM for the inhibition of hCAII activity. These compounds therefore have a similar CAII inhibitory potency to that of acetazolamide (IC(50)=25 nM), a known hCAII inhibitor. Docking studies have been performed with selected compounds to the crystal structure of hCAII and excellent correlation of scores with biological activity was observed. This agrees with our recent observations when we were the first to report the inhibition of hCAII by STS inhibitors. These studies and initial results with docking to the crystal structure of the extracellular domain of hCAXII indicate that the STS sulphamate ester inhibitors should also be interesting candidates to pursue as inhibitors of CA isozymes that are over-expressed in human tumours.

Antineoplastic Agents↗
PubMed1977

Effect of structure on the excretion of steroidal acids in human urine and their potential colorimetric assay as 17-oxogenic steroids.

Following the oral administration of tritiated coricosterone, cortisol, deoxycorticosterone and progesterone to human subjects, 14.9%, 12.8%, 3.4% and 2.1% of the dose was recovered in the acidic metabolite fraction of 48 h urines after conventional hydrolysis and solvent partition. Neutral and acidic 17-oxogenic steroids (17-OGS) excreted in 24 h urines were also measured with the Zimmermann color reaction. The acidic 17-IGS accounted for 14.1%, 16.4% and 12.1% of the fractionated 17-OGS in the urines of normal and pregnant females and normal males respectively. From structural considerations, it was concluded that only 17-hydroxylated steroidal acids, with a 20-hydroxy-21-oic acid side chain and derived predominantly from cortisol, would be estimated as 17-OGS after oxidation with sodium periodate. 17-Dexy steroidal acids resemble the neutral 17-deoxycorticosteroids in undergoing side chain oxication to 17-aldehydes which do not form Zimmermann chromogens. The excretion of both neutral and acidic 17-OGS was suppressible with dexamethasone administration.

17-Ketosteroids↗
PubMed1975

Liquid ion exchangers in paper chromatography of steroidal glucosiduronic acids, glucosiduronic esters and free steroids. Influence of concentration of exchanger and counterion.

The chromatographic mobility of steroidal glucosiduronic acids on paper in chloroform-formamide increases as the concentration of ion exchanger in the chloroform phase increases; mobility decreases as the concentration of counterion in formamide increases. Mobility of glucosiduronic esters and of hydroxylated free steroids increases with an increase in concentration of exchanger; small changes in concentration of counterion in the stationary phase do not alter the migration of these nonionizable compounds. Data are presented which suggest that partition of the glucosiduronic acids between the two phases occurs predominantly by an ion-exchange process and that hydrogen bonding plays a secondary role. Partition of the glucosiduronic esters and hydroxylated free steroids appears to occur primarily by a hydrogen-bonding process.

Cholesterol↗
PubMed1978

The effect of progesterone analogues, naturally occurring steroids, and contraceptive progestins on hypothalamic and anterior pituitary delta4-steroid (progesterone) 5alpha-reductase.

The effects of a number of steroids on the conversion of progesterone to 5alpha-dihydroprogesterone by hypothalamic and pituitary progesterone 5alpha-reductase have been investigated. Using enzyme preparations from female rats and 3H-progesterone as substrate, 5alpha-reduced products (5alpha-dihydroprogesterone and 3alpha-hydroxy-5alpha-pregnan-20-one) were analyzed by reverse isotopic dilution analysis. The amount of total 5alpha-reduced products formed was compared in the presence and absence of the test steroid. Derivatives lacking the delta4 and/or the 3-keto moiety were without effect. Corticosterone had no effect. 16beta-Methylprogesterone inhibited progesterone 5alpha-reduction in both tissues by at least 65%, while the 2alpha-, 6alpha-, and 7alpha-methylated derivatives had lesser effects. 3-Oxo-4-pregnene-20beta-carboxaldehyde and 21-fluoroprogesterone were potent inhibitors. 17-Hydroxyprogesterone was a competitive inhibitor (substrate) with Ki's of 0.27 micrometer (pituitary) and 0.29 micrometer (hypothalamus). Medroxyprogesterone exerted little inhibitory effect. Of the 19-nor-steroids examined, only norethindrone appreciably inhibited the 5alpha-reduction. These results suggest that some natural delta4-3-ketosteroids can modify enzymatic activity. Also, inhibitory analogues may be useful for studies on the role of this 5alpha-reduction of progesterone.

3-Hydroxysteroid Dehydrogenases↗
PubMed2001

Biphenyls as surrogates of the steroidal backbone. Part 2: discovery of a novel family of non-steroidal 5-alpha-reductase inhibitors.

A new family of non-steroidal 5-alpha-reductase inhibitors was designed by replacing the steroid skeleton of an inhibitor related to estrone by a biphenyl moiety. This hypothesis originated from the reported estrogenic activity of a few biphenyl compounds (see Part 1 of this paper; Lesuisse et al. Bioorg. Med. Chem. Lett. 2001, 11, 1709). Two compounds turned out to be potent type 2 5-alpha-reductase inhibitors with IC(50)'s of inhibition in the nanomolar range. These are to our knowledge amongst the most potent non-steroidal 5-alpha-reductase inhibitors described to date.

5-alpha Reductase Inhibitors↗
PubMed2002

Biosynthesis of steroids in ovarian follicles of red seabream, Pagrus major (Sparidae, Teleostei) during final oocyte maturation and the relative effectiveness of steroid metabolites for germinal vesicle breakdown in vitro.

The steroid synthesis pathway in the ovarian follicles of the red seabream during final oocyte maturation (FOM) was investigated by incubating intact follicles with different radioactively labeled steroid precursors. During FOM, the steroidogenic shift from estradiol-17beta to 20 beta-hydroxylated progestin production occurred mainly due to a combination of inactivation of C 1720-lyase and activation of 20 beta-hydroxysteroid dehydrogenase. Of the steroids produced, 1720 beta-dihydroxy-4-pregnen-3-one (1720 beta-P) and 1720 beta,21-trihydroxy-4-pregnen-3-one (20 beta-S) exhibited the greatest effect on germinal vesicle breakdown (GVBD) in vitro. 1720 beta-P was further converted to its 5 beta-reduced form, 1720 beta-dihydroxy-5 beta-pregnan-3-one (1720 beta-P-5 beta), which had lower GVBD activity, suggesting that 5 beta-reduction plays a role in the inactivation of the maturation-inducing ability of 1720 beta-P. In contrast, no 5 beta-reduced metabolite of 20 beta-S was found. Serum levels of 1720 beta-P and 20 beta-S, measured by ELISA, showed that circulating levels of both progestins increased during FOM, and 20 beta-S levels were approximately twice as high as 1720 beta-P levels. This study clarified the complete steroidogenesis pathway during FOM in red seabream ovarian follicles and showed that two 20 beta-hydroxylated progestins, 1720 beta-P and 20 beta-S, act as maturation-inducing hormones in this species. The catabolites of these two progestins and their physiological roles in reproduction are also discussed.

Animals↗
PubMed1992

Affinity labeling of human placental 3 beta-hydroxy-delta 5-steroid dehydrogenase and steroid delta-isomerase: evidence for bifunctional catalysis by a different conformation of the same protein for each enzyme activity.

3 beta-Hydroxy-delta 5-steroid dehydrogenase and steroid delta-isomerase copurify from human placental microsomes as a single enzyme protein. The affinity-alkylating secosteroid, 5,10-secoestr-4-yne-3,10,17-trione, inactivates the dehydrogenase and isomerase reactions in a time-dependent manner, but which of the two activities is targeted depends on the concentration of secosteroid. At 2-5 microM secosteroid, the dehydrogenase activity is alkylated in a site-specific manner (pregnenolone slows inactivation) that follows first-order inactivation kinetics (KI = 4.2 microM, k3 = 1.31 x 10(-2) min-1). As the secosteroid level increases from 11 to 30 microM, dehydrogenase is paradoxically inactivated at progressively slower rates, and pregnenolone no longer protects against the alkylator. The inactivation of isomerase exhibits the expected first-order kinetics (KI = 31.3 microM, k3 = 6.42 x 10(-2) min-1) at 11-30 microM secosteroid. 5-Androstene-3,17-dione protects isomerase from inactivation by 15 microM secosteroid, but the substrate steroid unexpectedly fails to slow the inactivation of isomerase by a lower concentration of alkylator (5 microM). A shift from a dehydrogenase to an isomerase conformation in response to rising secosteroid levels explains these results. Analysis of the ligand-induced conformational change along with cofactor protection data suggests that the enzyme expresses both activities at a bifunctional catalytic site. According to this model, the protein begins the reaction sequence as 3 beta-hydroxysteroid dehydrogenase. The products of the first step (principally NADH) promote a change in protein conformation that triggers the isomerase reaction.

3-Hydroxysteroid Dehydrogenases↗
PubMed1995

New steroidal antiinflammatory antedrugs: steroidal [16 alpha,17 alpha-d]-3'-carbethoxyisoxazolines.

Novel steroidal antiinflammatory antedrugs, 11 beta,20-dihydroxy-3,20-dioxo-3'-(ethoxycarbonyl)-isoxazolino[16,17 - d]pregna-1,4-diene (2a) and 9-fluoro-11 beta,20-dihydroxy-3,20-dioxo-3'-ethoxy- carbonylisoxazolino[16,17-d]pregna-1,4-diene (2b) were prepared in 97% yield via 1,3-dipolar cycloaddition of carbethoxyformonitrile (CEFNO) to 11 beta,21-dihydroxy-3,20-dioxopregna-1,4,-16-triene (1a) and 11 beta,21-dihydroxy-3,20-dioxo-9-fluoropregna-1,4,16-triene (1b), respectively, which were prepared via five steps from prednisolone and 9-fluoroprednisolone, respectively. The treatment of steroids 2a and 2b with acetic anhydride in pyridine led to the corresponding 21-acetates 3a and 3b, respectively, in 95% yield. Dose-response profiles of the croton oil-induced ear edema bioassay in rats were used to calculate the following ID50 values (nmol/ear resulting in a 50% reduction of edema): prednisolone (P), 540 nmol; 2b, 135 nmol; and 3b, 101 nmol. Inhibition of edema did not exceed 50% following application of either 2a or 3a. Relative potency calculations indicated that 2b was 4-fold and 3b 5.3-fold more potent than the parent compound P when applied topically. No significant adverse systemic effects were seen following treatments with 3b. These results suggest that C-9-fluorination, side-chain hydroxy group esterification, and [16 alpha,17 alpha-d]-3'-carbethoxyisoxazoline additions to the conventional steroid P improve topical antiinflammatory activity without concomitant increases in adverse systemic activity.

Animals↗
PubMed1995

Structure-activity relationships for inhibition of type 1 and 2 human 5 alpha-reductase and human adrenal 3 beta-hydroxy-delta 5-steroid dehydrogenase/3-keto-delta 5-steroid isomerase by 6-azaandrost-4-en-3-ones: optimization of the C17 substituent.

A variety of C17 amide-substituted 6-azaandrost-4-en-3-ones were prepared and tested versus human type 1 and 2 steroid 5 alpha-reductase (5AR) and human adrenal 3 beta-hydroxy-delta 5-steroid dehydrogenase/3-keto-delta 5-steroid isomerase (3BHSD) in order to optimize potency versus both isozymes of 5AR and selectivity versus 3BHSD. Two series of potent and selective C17 amides were discovered, 2,5-disubstituted anilides and (arylcycloalkyl)amides. Compounds from each series with picomolar IC50's versus human type 2 5AR and low nanomolar to picomolar IC50's versus human type 1 5AR possessing 100-500-fold selectivity versus 3BHSD were identified. A conformational model to predict 3BHSD potency was developed which could rationalize 3BHSD potency within three different series of compounds. Evaluation of some optimal compounds from this series in a chronic castrated rat model of 5AR inhibitor induced prostate involution, and pharmacokinetic measurements identified compounds (9, 12, 16, and 29) with good in vivo efficacy and half-life in the dog. An intact rat model of in vivo selectivity for 5AR versus 3BHSD inhibition was also developed. Dual inhibitors of both human 5AR's may show advantages over type 2 selective 5AR inhibitors, such as finasteride (1), in the treatment of disease states which depend upon dihydrotestosterone.

3-Hydroxysteroid Dehydrogenases↗