4,5-Disubstituted cis-pyrrolidinones as inhibitors of type II 17β-hydroxysteroid dehydrogenase. Part 3. Identification of lead candidate

Wood, Jill E.; Bagi, Cedo M.; Akuche, Christiana; Bacchiocchi, Antonietta; Baryza, Jeremy; Blue, Marie‐Luise; Brennan, Catherine A.; Campbell, Ann-Marie; Choi, Soongyu; Cook, Jack; Conrad, Patricia J.; Dixon, B. Romanowska; Ehrlich, Paul; Gane, Todd; Gunn, David; Joe, Ted; Johnson, Jeffrey S.; Jordan, Jerold; Kramss, Richard H.; Liu, Peiying; Levy, Joan; Lowe, Derek; McAlexander, Ian; Natero, Reina; Redman, Anikó M.; Scott, William J.; Town, Christopher; Wang, Ming; Wang, Yamin; Zhang, Zhonghua

doi:10.1016/j.bmcl.2006.06.041

Cited by 29 publications

(18 citation statements)

References 5 publications

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“…Some steroidal [5][6][7] and non steroidal [8,9] 17β-HSD2 inhibitors are already described. In our group we also developed and reported about several classes of non-steroidal 17β-HSD2 inhibitors [10][11][12][13][14], with a strong inhibition of human 17β-hydroxysteroid dehydrogenase type 2 (h17β-HSD2) and a good selectivity toward h17β-HSD1.…”

Section: Introductionmentioning

confidence: 99%

Metabolic stability optimization and metabolite identification of 2,5-thiophene amide 17β-hydroxysteroid dehydrogenase type 2 inhibitors

Gargano¹,

Perspicace²,

Hanke³

et al. 2014

European Journal of Medicinal Chemistry

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Section: Introductionmentioning

confidence: 99%

Metabolic stability optimization and metabolite identification of 2,5-thiophene amide 17β-hydroxysteroid dehydrogenase type 2 inhibitors

Gargano¹,

Perspicace²,

Hanke³

et al. 2014

European Journal of Medicinal Chemistry

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“…All generated models were based on the common chemical features of two training compounds, respectively, that were collected from the literature: model 1 on 5 (31) and 6 , 22 model 2 on 5 and 7 , 22 and model 3 on 7 and 8 , 24 respectively (Figure 3). The selection of these two molecules as training sets for each model was based on their structural diversity and potency.…”

Section: Resultsmentioning

confidence: 99%

Ligand-Based Pharmacophore Modeling and Virtual Screening for the Discovery of Novel 17β-Hydroxysteroid Dehydrogenase 2 Inhibitors

et al. 2014

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17β-Hydroxysteroid dehydrogenase 2 (17β-HSD2) catalyzes the inactivation of estradiol into estrone. This enzyme is expressed only in a few tissues, and therefore its inhibition is considered as a treatment option for osteoporosis to ameliorate estrogen deficiency. In this study, ligand-based pharmacophore models for 17β-HSD2 inhibitors were constructed and employed for virtual screening. From the virtual screening hits, 29 substances were evaluated in vitro for 17β-HSD2 inhibition. Seven compounds inhibited 17β-HSD2 with low micromolar IC50 values. To investigate structure–activity relationships (SAR), 30 more derivatives of the original hits were tested. The three most potent hits, 12, 22, and 15, had IC50 values of 240 nM, 1 μM, and 1.5 μM, respectively. All but 1 of the 13 identified inhibitors were selective over 17β-HSD1, the enzyme catalyzing conversion of estrone into estradiol. Three of the new, small, synthetic 17β-HSD2 inhibitors showed acceptable selectivity over other related HSDs, and six of them did not affect other HSDs.

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“…51 A novel, operationally simple, three-component assembly of these privileged structures, based on readily available furancarbaldehydes 64, anilines 65, and cyclopropanated N-Boc pyrrole 66, was reported in 2012 (Scheme 16). 52 Among a number of Lewis acids screened, Sc(OTf) 3 was found to be the optimal catalyst for the transformation.…”

Section: Scheme 15 Sc(otf) 3 -Catalyzed Three-component Reactionmentioning

confidence: 99%

Recent applications of rare-earth metal(III) triflates in cycloaddition and cyclization reactions

Ladziata¹

2014

Arkivoc

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Rare-earth metal(III) triflates are extremely mild, efficient and water-tolerable Lewis acid catalysts for a wide range of organic transformations. Rare-earth metal triflates retain activity even in the presence of multiple Lewis bases containing oxygen, nitrogen, sulfur and phosphorus atoms, and can be easily recovered and reused without any loss of catalytic activity. This review summarizes recent developments and highlights key applications of these unique Lewis acids in cycloaddition and cyclization reactions.

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4,5-Disubstituted cis-pyrrolidinones as inhibitors of type II 17β-hydroxysteroid dehydrogenase. Part 3. Identification of lead candidate

Cited by 29 publications

References 5 publications

Metabolic stability optimization and metabolite identification of 2,5-thiophene amide 17β-hydroxysteroid dehydrogenase type 2 inhibitors

Metabolic stability optimization and metabolite identification of 2,5-thiophene amide 17β-hydroxysteroid dehydrogenase type 2 inhibitors

Ligand-Based Pharmacophore Modeling and Virtual Screening for the Discovery of Novel 17β-Hydroxysteroid Dehydrogenase 2 Inhibitors

Recent applications of rare-earth metal(III) triflates in cycloaddition and cyclization reactions

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