Tetrahydroisoquinolines as subtype selective estrogen agonists/antagonists

Chesworth, Richard; Zawistoski, Michael P.; Lefker, Bruce A.; Cameron, Kimberly O.; Day, Robert; Mangano, F.Michael; Rosati, Robert L.; Colella, Stacy; Petersen, Donna N.; Brault, Amy; Lu, Bihong; Pan, Lydia C.; Perry, Pia; Ng, Oicheng; Castleberry, Tessa A.; Owen, Thomas A.; Brown, Thomas A.; Thompson, David D.; DaSilva-Jardine, Paul

doi:10.1016/j.bmcl.2004.03.077

Cited by 39 publications

(17 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2'-Methyl analog 57 showed a higher receptor affinity than Raloxifene. Replacement of the 2-aryl group by a methyl (58), isopropyl (59), 2'-thienyl (60) or 4-hydroxybenzyl group (61) largely preserved binding affinity, whereas replacement by a cyclohexyl (62) 35 30 Katzenellenbogen and coworkers prepared three fluoroalkyl Raloxifene analogs as model systems for 18 F labeled SERMs that can be used as imaging agents for positron emission tomography (PET). 1-Fluoro-ethyl and propyl chains were attached to the 2'-position of Raloxifene.…”

Section: Rba Er (%) Rba Er (%) /mentioning

confidence: 98%

“…Introduction of a methyl group at the 1-position was well tolerated and resulted in minor differences on receptor affinity and ERα selectivity. However, compound 161 showed a 6-fold increase in inhibition of transcriptional activity through ERE in a human cervix adenocarcinoma cell Scientist from Pfizer recently reported on related tetrahydroisoquinolines, decorated with alternative Nsubstituents including benzyls, arylsulfonyls and amides [58]. Initially, 1,2-disubstituted isoquinolines without a BSC were investigated.…”

Section: Tetrahydroisoquinolinesmentioning

confidence: 98%

See 1 more Smart Citation

Non-Steroidal Subtype Selective Estrogens

Veeneman¹

2005

CMC

View full text Add to dashboard Cite

The biological effects of estrogens are thought to be mediated by two receptors referred to as ERalpha and ERbeta. In recent years significant efforts have been devoted to the design of subtype selective ligands. These ligands are valuable tools to establish the precise biological role of each of the subtypes and to develop new generations of therapeutics. The first part of this review briefly summarizes the biology behind the estrogen receptors. The second part addresses the structure-activity relationship of the subtype selective ER ligands that were reported up to now. In the third part, the current insights in the therapeutic prospects of the subtype selective estrogens will be discussed.

show abstract

Section: Rba Er (%) Rba Er (%) /mentioning

confidence: 98%

Section: Tetrahydroisoquinolinesmentioning

confidence: 98%

Non-Steroidal Subtype Selective Estrogens

Veeneman¹

2005

CMC

View full text Add to dashboard Cite

show abstract

“…Tetrahydroisoquinolines (THIQs) are common motifs in natural and synthetic compounds with interesting biological activity. [13] Reports on the use of THIQs for the generation of SERMs [14] encouraged our selection of this heterocycle as a prototypical mimic of the estrane A,B-ring system. We envisaged that the C-2 and C-3 pharmacophore elements of the steroidal A-ring could be introduced at C-7 and C-6 respectively of the THIQ core.…”

Section: Introductionmentioning

confidence: 99%

Tetrahydroisoquinolinone‐Based Steroidomimetic and Chimeric Microtubule Disruptors

et al. 2013

View full text Add to dashboard Cite

A SAR translation strategy was used for the discovery of tetrahydroisoquinoline (THIQ)-based steroidomimetic and chimeric microtubule disruptors based upon a steroidal starting point. A steroid A,B-ring-mimicking THIQ core was connected to methoxy aryl D-ring ring mimics through methylene, carbonyl and sulfonyl linkers to afford a number of steroidomimetic hits (e.g. 20c GI50 2.1 μM). Optimisation and control experiments demonstrate the complementary SAR of this series and the steroid derivatives that inspired its design. Linkage of the THIQ-based A,B-mimic with the trimethoxy aryl motif prevalent in colchicine site binding microtubule disruptors delivered a series of chimeric molecules whose activity (to GI50 40 nM) surpasses that of the parent steroid derivatives. Validation of this strategy was obtained from the excellent oral activity of 20z relative to a benchmark steroidal bis-sulfamate in an in vivo model of multiple myeloma.

show abstract

“…Tetrahydroisoquinoline (THIQ)-based systems appeared ideal for this purpose since they possess a good degree of the rigidity present in the steroidal system, the N -2 nitrogen offers an achiral site of attachment for library generation, and a convergent, flexible entry to screening candidates could be envisaged (Figure 1). Furthermore, precedent for the successful use of tetrahydroisoquinolines in the generation of selective estrogen receptor modulators was available, 15 and we have recently applied the same template for the generation of chimeric microtubule disruptors. 16 We now describe how this approach was used to discover a new series of microtubule disruptors optimized to surpass, in many respects, the steroidal template that inspired their design.…”

mentioning

confidence: 99%

Steroidomimetic Tetrahydroisoquinolines for the Design of New Microtubule Disruptors

Leese

Jourdan

Döhle

et al. 2011

ACS Med. Chem. Lett.

View full text Add to dashboard Cite

Structure–activity relationship translation offers an expeditious means for discovery of new active series. This approach was applied to discover tetrahydroisoquinoline (THIQ)-based steroidomimetic microtubule disruptors. The two A-ring elements of a three-point steroidal pharmacophore were incorporated into a THIQ-based A,B-ring mimic to which an H-bond acceptor was attached as the third motif. Optimization of the representative 6c through conformational biasing delivered a 10-fold gain in activity and a new series of microtubule disruptors (e.g., 9c) with antiproliferative activity in the nanomolar range. The THIQ derivatives match, or surpass, the activities of the steroidal series and exhibit improved physicochemical properties.

show abstract

Tetrahydroisoquinolines as subtype selective estrogen agonists/antagonists

Cited by 39 publications

References 15 publications

Non-Steroidal Subtype Selective Estrogens

Non-Steroidal Subtype Selective Estrogens

Tetrahydroisoquinolinone‐Based Steroidomimetic and Chimeric Microtubule Disruptors

Steroidomimetic Tetrahydroisoquinolines for the Design of New Microtubule Disruptors

Contact Info

Product

Resources

About