Synthesis of compounds 19–25.

<p>Reagents and conditions: (a) pyridine, 100°C, 20 h, for <b>19i</b>: <i>p</i>-methoxybenzoylchloride, for <b>21i</b>: <i>m</i>-methoxybenzoylchloride, for <b>22i</b>: <i>m</i>-methoxyphenylsulfochloride, for compound <b>23i</b>: <i>m</i>-methoxybenzoisocyanate, for <b>24i</b>: <i>m</i>-methoxybenzoisothiocyanate, for compound <b>25i</b>: <i>m</i>-methoxybenzylchloride; (b) for <b>19–21</b>, BF₃S(CH₃)₂, anhydrous CH₂Cl₂, rt, 20 h; for <b>22–25</b>, BBr₃, CH₂Cl₂, −78°C to rt, 20 h.</p

Steroidal ligands co-crystallized with 17β-HSD1.

<p>The five steroidal ligands cocrystalized with 17β-HSD1s that were used to build the pharmacophore model. Structural information was taken from the protein data bank(PDB-ID: 1a27, 1equ, 1dht, 1i5r, and 3hb5, respectively).</p

Interactions found in the complexes between 6, 21 and the five 17β-HSD1 crystal structures used to build up the pharmacophore, respectively.

a<p>Distance (Å) between the heteroatoms for H-bonds (H) and between centroids or centroid and cation for π-interactions (π).</p

Nonsteroidal 17β-HSD1 inhibitors published by our group.

<p>Nonsteroidal 17β-HSD1 inhibitors published by our group.</p

Synthesis of compounds 6–18.

<p>Reagents and conditions: (a) 1) NaNO₂, H₃PO₄ (85%), −10°C, 20 min, 2) H₃PO₂, H₃PO₄ (85%), −10°C to rt, 20 h; (b) 1) nBuLi, anhydrous THF, −70°C to −20°C, 1 h, 2) for <b>6ii</b> and <b>12ii</b>: <i>m</i>-methoxybenzaldehyde, for <b>9ii</b>: <i>p</i>-methoxybenzaldehyde, for <b>15i</b>: <i>o</i>-methoxybenzoisocyanate, for <b>17i</b>: <i>m</i>-methoxybenzoisocyanate, anhydrous THF, −15°C, 90 min; (c) for <b>6i</b>, <b>12i</b> and <b>13i</b>, SIBX, anhydrous THF, 0°C to 60°C, 20 h; for <b>10</b> and <b>11i</b>: TMSiCl, NaI, CH₃CN, reflux, 20 h; (d) for <b>6–9</b> and <b>15–18</b>: BF₃S(CH₃)₂, anhydrous CH₂Cl₂, rt, 20 h; for compounds <b>11–14</b>, pyridinium hydrochloride, 220°C, 4 h.</p

Lead Optimization of 17β-HSD1 Inhibitors of the (Hydroxyphenyl)naphthol Sulfonamide Type for the Treatment of Endometriosis

The reduction of estrone to estradiol, the most potent estrogen in human, is catalyzed by 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1). A promising approach for the treatment of estrogen-dependent diseases is the reduction of intracellular estradiol formation by inhibition of 17β-HSD1. For the species-specific optimization of the (hydroxyphenyl)­naphthols, a combinatorial approach was applied and enhanced by a focused synthesis that resulted in the aromatic-substituted (hydroxyphenyl)­naphthol sulfonamides. Rigidification of <b>12</b> led to the 4-indolylsulfonamide <b>30</b>, which is a highly active and selective human 17β-HSD1 inhibitor, as well as a highly potent and selective inhibitor of 17β-HSD1 from <i>Callithrix jacchus</i>. It shows no affinity to the estrogen receptors α and β and good intracellular activity (T47D). Thus, compound <b>30</b> shows good properties for further ADMET studies and might be a candidate for the in vivo proof of concept in <i>C. jacchus</i>