ChemInform Abstract: ANTIIMPLANTATION AGENTS: PART II ‐ 1,2‐DIARYL‐1,2,3,4‐TETRAHYDROISOQUINOLINES

Nagarajan, K.; Talwalker, P. K.; Kulkarni, C. L.; Shah, R. K.; Shenoy, S. J.; Prabhu, S.

doi:10.1002/chin.198522216

Cited by 4 publications

(10 citation statements)

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“…High throughput screening of our sample collection using a binding assay led to the identification of tetrahydroisoquinoline 27 (Figure ), a substance which had been reported as an antiimplantation agent . Not unexpectedly, compound 27 lacked antagonist activity in the MCF-7 cellular assay despite its affinity for ERα (IC 50 = 285 nM, Table ).…”

Section: Resultsmentioning

confidence: 99%

“…The tetrahydroisoquinolines were initially prepared via a route involving a Bischler-Napieralski cyclization reaction as outlined in Scheme 1. 15 3-Benzyloxyphenylacetyl chloride (9), prepared in two steps from 3-hydroxyphenylacetic acid, was transformed into the amide 10 by treatment with aniline. LAH-mediated reduction of 10 led to the aniline derivative 11 which, upon reaction with 4-allyloxybenzoyl chloride (8), furnished amide 12.…”

Section: Chemistrymentioning

confidence: 99%

“…The tetrahydroisoquinolines were initially prepared via a route involving a Bischler−Napieralski cyclization reaction as outlined in Scheme . 3-Benzyloxyphenylacetyl chloride ( 9 ), prepared in two steps from 3-hydroxyphenylacetic acid, was transformed into the amide 10 by treatment with aniline.…”

Section: Chemistrymentioning

confidence: 99%

“…(a) The methoxy analogues of 17a and 18a were disclosed in an earlier publication, the pyrrolidinoethoxy derivative showing antiimplantation activity while the piperidinoethoxy analogue did not. See ref .…”

Section: Referencesmentioning

confidence: 99%

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Estrogen Receptor Modulators: Identification and Structure−Activity Relationships of Potent ERα-Selective Tetrahydroisoquinoline Ligands

et al. 2003

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As part of a program aimed at the development of selective estrogen receptor modulators (SERMs), tetrahydroisoquinoline derivative 27 was discovered by high throughput screening. Successive replacements of the p-F substituent of 27 by an aminoethoxy side chain and of the 1-H of the tetrahydroisoquinoline core by a 1-Me group provided analogues 19 and 20. These compounds showed potencies in a cell-based reporter gene assay (ERE assay) varying between 0.6 and 20 nM and displayed antagonist behaviors in the MCF-7 human breast adenocarcinoma cell line with IC(50)s in the range of 2-36 nM. The effect of N-phenyl substituents on the activity and pharmacokinetic properties of tetrahydroisoquinoline analogues was explored. As a result of this investigation, two potent derivatives bearing a p-F N-aryl group, 19c and 20c, were discovered as candidates suitable for further profiling. To gain insight into the ligand-receptor interaction, the X-ray crystallographic structure of the 1-H tetrahydroisoquinoline derivative (R)-18a in complex with ERalpha-ligand binding domain (LBD)(301)(-)(553)/C-->S triple mutant was solved to 2.28 A. An overlay of this X-ray crystal structure with that reported for the complex of ERalpha-LBD(301)(-)(553)/carboxymethylated C and raloxifene (5) shows that both compounds bind to the same cleft of the receptor and display comparable binding modes, with differences being observed in the conformation of their "D-ring" phenyl groups.

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Section: Resultsmentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

Section: Referencesmentioning

confidence: 99%

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Estrogen Receptor Modulators: Identification and Structure−Activity Relationships of Potent ERα-Selective Tetrahydroisoquinoline Ligands

et al. 2003

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“…Synthesis of Intermediate Tetrahydroisoquinoline 13 via the Bischler − Napieralski Route. 3-Hydroxyphenylacetic acid ( 8 ) was transformed into tetrahydroisoquinoline 13 following a similar strategy as described in the literature for related compounds (Scheme ) . Selective benzylation of 3-hydroxyphenylacetic acid was accomplished readily by trapping the dianion formed upon KOH treatment (2.5 equiv) with benzyl bromide (1.05 equiv) .…”

Section: Chemistrymentioning

confidence: 99%

Selective Estrogen Receptor Modulators with Conformationally Restricted Side Chains. Synthesis and Structure−Activity Relationship of ERα-Selective Tetrahydroisoquinoline Ligands

et al. 2004

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We disclose herein the discovery of estrogen receptor alpha (ERalpha) selective estrogen receptor modulators (SERMs) of the tetrahydroisoquinoline series that incorporate novel conformationally restricted side chains as replacement of the aminoethoxy residue typical of SERMs. Molecular modeling studies used in conjunction with the X-ray crystal structure of the ERalpha ligand binding domain (LBD) with raloxifene (7) suggested a diazadecaline moiety as a viable mimic of the SERM side chain. On the basis of this knowledge, the piperidinylethoxy moiety of our lead compound 60 was replaced by a diazadecaline subunit, providing the novel tetrahydroisoquinoline 29. In addition to exhibiting a binding affinity to ERalpha and antagonistic properties in the estrogen response element and MCF-7 assays similar to those of the parent compound 60, ligand 29 showed a reduced agonist behavior in the MCF-7 assay in the absence of 17beta-estradiol. These data point toward the fact that 29 may have a potential for breast cancer prevention/treatment in vivo, a feature which is particularly attractive in the quest for safe alternatives to hormone replacement therapy. In a pharmacokinetic experiment carried out in rats, 29 displayed an interesting profile, with a bioavailability of 49%. We also disclose the X-ray crystal structure of 29 in complex with ERalpha-LBD, which reveals the preferred configurations of 29 at the two chiral centers and the details of its interactions with the receptor. Finally, our structure-activity relationship studies show that other analogues bearing constrained side chains retain potency and antagonist activity and that a 3-OH substituted phenyl D-ring increases the selectivity of a set of piperazinyl-containing ligands in favor of ERalpha over ERbeta.

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Rational approaches of drug design for the development of selective estrogen receptor modulators (SERMs), implicated in breast cancer

Makar

Saha

Swetha

et al. 2020

Bioorganic Chemistry

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ChemInform Abstract: ANTIIMPLANTATION AGENTS: PART II ‐ 1,2‐DIARYL‐1,2,3,4‐TETRAHYDROISOQUINOLINES

Abstract: Aus den Phenylessigsäureaniliden (I) werden über die Amide (II) die Diaryl‐tetrahydroisochinoline (III) hergestellt, die ebenso wie eine Reihe ähnlicher Verbindungen wie (lW‐(VII) werden (zum Teil IR‐.

Cited by 4 publications

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Estrogen Receptor Modulators: Identification and Structure−Activity Relationships of Potent ERα-Selective Tetrahydroisoquinoline Ligands

Estrogen Receptor Modulators: Identification and Structure−Activity Relationships of Potent ERα-Selective Tetrahydroisoquinoline Ligands

Selective Estrogen Receptor Modulators with Conformationally Restricted Side Chains. Synthesis and Structure−Activity Relationship of ERα-Selective Tetrahydroisoquinoline Ligands

Rational approaches of drug design for the development of selective estrogen receptor modulators (SERMs), implicated in breast cancer

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