Benzopyrans as selective estrogen receptor beta agonists (SERBAs). Part 5: Combined A- and C-ring structure-activity relationship studies.

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Richardson TI, Dodge JA, Wang Y, Durbin JD, Krishnan V, Norman BH

Benzopyrans as selective estrogen receptor beta agonists (SERBAs). Part 5: Combined A- and C-ring structure-activity relationship studies.

Bioorg Med Chem Lett. 2007 Oct 15;17(20):5563-6. Epub 2007 Aug 11.

PubMed ID
17804226 [ View in PubMed
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Abstract

Benzopyrans are selective estrogen receptor (ER) beta agonists (SERBAs), which bind the ER subtypes alpha and beta in opposite orientations. Here we describe the synthesis of a late stage intermediate that allowed us to combine A-ring and C-ring modifications and carry out simultaneous SAR studies at both positions. Modification of both positions proved additive, maintaining affinity and improving ERbeta selectivity up to 83-fold. An X-ray cocrystal structure confirms the previously observed binding mode in ERbeta.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
(3AS,4R,9BR)-2,2-DIFLUORO-4-(4-HYDROXYPHENYL)-1,2,3,3A,4,9B-HEXAHYDROCYCLOPENTA[C]CHROMEN-8-OLEstrogen receptor alphaKi (nM)8.47.522Details
(3AS,4R,9BR)-2,2-DIFLUORO-4-(4-HYDROXYPHENYL)-1,2,3,3A,4,9B-HEXAHYDROCYCLOPENTA[C]CHROMEN-8-OLEstrogen receptor betaKi (nM)0.447.522Details
(3aS,4R,9bR)-2,2-difluoro-4-(4-hydroxyphenyl)-6-(methoxymethyl)-1,2,3,3a,4,9b-hexahydrocyclopenta[c]chromen-8-olEstrogen receptor betaKi (nM)0.537.522Details
(3AS,4R,9BR)-4-(4-HYDROXYPHENYL)-6-(METHOXYMETHYL)-1,2,3,3A,4,9B-HEXAHYDROCYCLOPENTA[C]CHROMEN-8-OLEstrogen receptor alphaKi (nM)11.97.522Details
(3AS,4R,9BR)-4-(4-HYDROXYPHENYL)-6-(METHOXYMETHYL)-1,2,3,3A,4,9B-HEXAHYDROCYCLOPENTA[C]CHROMEN-8-OLEstrogen receptor betaKi (nM)0.287.522Details
ErteberelEstrogen receptor alphaKi (nM)2.77.522Details
ErteberelEstrogen receptor betaKi (nM)0.197.522Details