- Treatment of estrogen-dependent diseases: Design, synthesis and profiling of a selective 17β-HSD1 inhibitor with sub-nanomolar IC50for a proof-of-principle study
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Current endocrine therapeutics for the estrogen-dependent disease endometriosis often lead to considerable side-effects as they act by reducing estrogen action systemically. A more recent approach takes advantage of the fact that the weak estrogen estrone (E1) which is abundant in the plasma, is activated in the target cell to the highly estrogenic estradiol (E2) by 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1). 17β-HSD1 is overexpressed in endometriosis and thus a promising target for the treatment of this disease, with the prospect of less target-associated side-effects. Potent inhibitors from the class of bicyclic substituted hydroxyphenylmethanones with sulfonamide moiety recently described by us suffered from high molecular weight and low selectivity over 17βHSD2, the physiological adversary of 17β-HSD1. We describe the structural optimizations leading to the discovery of (5-(3,5-dichloro-4-methoxyphenyl)thiophen-2-yl)(2,6-difluoro-3-hydroxyphenyl)methanone 20, which displayed a sub-nanomolar IC50towards 17β-HSD1 as well as high selectivity over the type 2 enzyme, the estrogen receptors α and β and a range of hepatic CYP enzymes. The compound did neither show cellular toxicity, nor PXR activation nor mutagenicity in the AMES II assay. Additional favourable pharmacokinetic properties (rat) make 20 a suitable candidate for proof-of-principle studies using xenotransplanted immunodeficient rats.
- Abdelsamie, Ahmed S.,van Koppen, Chris J.,Bey, Emmanuel,Salah, Mohamed,B?rger, Carsten,Siebenbürger, Lorenz,Laschke, Matthias W.,Menger, Michael D.,Frotscher, Martin
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p. 944 - 957
(2017/02/18)
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- 5H-PYRROLO[3,4-£>]PYRAZIN-7-AMINE DERIVATIVES INHIBITORS OF BETA-SECRETASE
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The present invention relates to novel compounds of formula (I) and their pharmaceutical compositions. In addition, the present invention relates to therapeutic methods for the treatment and/or prevention of Aβ-related pathologies such as Downs syndrome, β- amyloid angiopathy such as but not limited to cerebral amyloid angiopathy or hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as but not limited to MCI ("mild cognitive impairment"), Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with diseases such as Alzheimer disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
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Page/Page column 32
(2011/02/24)
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- A REGIOSPECIFIC SYNTHESIS OF CARBAZOLES VIA CONSECUTIVE PALLADIUM-CATALYZED CROSS-COUPLING AND ARYNE-MEDIATED CYCLIZATION
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A regiospecific synthesis of carbazoles has been developed using palladium-catalyzed cross-coupling of N-(tert-butoxycarbonyl)-2-tributylstannylanilines with 2- or 3-bromochlorobenzene followed by aryne-mediated cyclization as the key reactions.The carbazole alkaloids, glycozolinine and glycozolidine, were synthesized using this procedure.
- Iwao, Masatomo,Takehara, Hirokazu,Furukawa, Sunao,Watanabe, Mitsuaki
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p. 1483 - 1488
(2007/10/02)
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- A Novel Class of "GABAergic" Agents: 1-Aryl-3-(aminoalkylidene)oxindoles
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Antagonism of mercaptopropionic acid (MPA) induced convulsions, reflecting a GABAergic mechanism, was observed in a series of 1-aryl-3-(aminoalkylidene)oxindoles.Optimal MPA antagonism was associated with 3-halo, 3-alkyl, and/or 4-alkoxy substituents in the pendant aryl ring and with (dimethylamino)methylene, 1-(dimethylamino)ethylidene and N-methyl-2-pyrrolidinylidene side chains.The precise mechanism of action of these agents is unclear at this time; however, they are not GABA mimics and they do not affect GABA levels.Like other GABAergic agents, these compounds are potent enhancers of benzodiazepine binding and they antagonize cyclic GMP elevations induced by isoniazid.Compounds from this series may therefore have potential therapeutic utility as anticonvulsants or anxiolytics.
- Sarges, Reinhard,Howard, Harry R.,Koe, B. Kenneth,Weissman, Albert
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p. 437 - 444
(2007/10/02)
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- Heteroylidene indolone compounds
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Certain substituted 1-phenyl-3-(aminoalkylidene)-2(1H,3H)-indolones are highly potent gabaergic agents, valuable in the treatment of individuals suffering from schizophrenia or reversing the side effects of a previously or concurrently administered neuroleptic agent; or in the treatment of epilepsy. A wider class of substituted 1-phenyl-3-(aminoalkylidene)-2(1H,3H)-indolones, together with 1-phenyl-3-(2-pyrrolidinylidene)-2(1H,3H)-indolones, and homologs thereof, are valuable in the treatment of anxiety.
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