Novel 2,3-Dihydrobenzofuran-2-carboxylic Acids:  Highly Potent and Subtype-Selective PPARα Agonists with Potent Hypolipidemic Activity

Shi, Guo Q.; Dropinski, James F.; Zhang, Yong; Santini, Conrad; Sahoo, Soumya P.; Berger, Joel P.; MacNaul, Karen L.; Zhou, Gaochao; Agrawal, Arun K.; Alvaro, Raul; Cai, Tian-Quan; Hernandez, Melba; Wright, Samuel D.; Moller, David E.; Heck, James V.; Meinke, Peter T.

doi:10.1021/jm050373g

Cited by 91 publications

(30 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…First, we found out that all 30 PPAR agonists mapped by HRV coat protein models were agonists for PPAR-a and that none of them belonged to the six fatty acids from the PPAR ligand test set. Second, we noticed that all of them could be assigned to three structurally similar groups: The (2R)-2-methylchromane-2-carboxylic acid derivatives, the 2,3-dihydrobenzofuran-2-carboxylic acid analogues, and the propionic acid derivatives [31][32][33].…”

Section: B Resultsmentioning

confidence: 99%

Pharmacophore modeling and parallel screening for PPAR ligands

Markt

Schuster

Kirchmair

et al. 2007

J Comput Aided Mol Des

View full text Add to dashboard Cite

We describe the generation and validation of pharmacophore models for PPARs, as well as a large scale validation of the parallel screening approach by screening PPAR ligands against a large database of structure-based models. A large test set of 357 PPAR ligands was screened against 48 PPAR models to determine the best models for agonists of PPAR-alpha, PPAR-delta, and PPAR-gamma. Afterwards, a parallel screen was performed using the 357 PPAR ligands and 47 structure-based models for PPARs, which were integrated into a 1537 models comprising in-house pharmacophore database, to assess the enrichment of PPAR ligands within the PPAR hypotheses. For these purposes, we categorized the 1537 database models into 181 protein targets and developed a score that ranks the retrieved targets for each ligand. Thus, we tried to find out if the concept of parallel screening is able to predict the correct pharmacological target for a set of compounds. The PPAR target was ranked first more often than any other target. This confirms the ability of parallel screening to forecast the pharmacological active target for a set of compounds.

show abstract

Section: B Resultsmentioning

confidence: 99%

Pharmacophore modeling and parallel screening for PPAR ligands

Markt

Schuster

Kirchmair

et al. 2007

J Comput Aided Mol Des

View full text Add to dashboard Cite

show abstract

“…Interestingly, it was found that (S)-88 and (R)-89 were about 400 times more potent than their respective isomers. This stereoselectivity was far superior compared to that previously reported for other PPAR ligands probably due to the additional conformational constraint imposed by the rigid cyclic structure [110]. It is to be noted that (S)-88 and (R)-89 only apparently have opposite absolute configurations.…”

Section: -Substituted Aryloxyacetic Acid Derivatives (Fibrates)mentioning

confidence: 52%

Structural Insight Into the Crucial Role of Ligand Chirality in the Activation of PPARs by Crystallographic Methods

Loiodice

Pochetti²

2011

CTMC

View full text Add to dashboard Cite

Peroxisome Proliferator-Activated Receptors (PPARs) are ligand-activated transcription factors that govern lipid and glucose homeostasis playing a central role in cardiovascular disease, obesity, and diabetes. These receptors show a high degree of stereoselectivity towards several classes of drugs. This review provides an overview of most papers reporting the influence of stereochemistry on PPAR activation. Some cases in which chirality is a crucial point in determining the PPAR binding mode are reviewed and discussed with the aim to show how enantiomeric recognition originates at the molecular level. The structural characterization by crystallographic methods of complexes formed by PPARs with their ligands turns out to be an essential tool to explain receptor stereoselectivity.

show abstract

“…For the synthesis of chroman derivative 2 , first a base-mediated intramolecular S N Ar reaction was envisioned for the aryl C–O bond formation under transition-metal-free conditions [28–30]. The additional benefit of this strategy would be the non-requirement of any protecting group to construct the chroman ring.…”

Section: Resultsmentioning

confidence: 99%

Studies directed toward the exploitation of vicinal diols in the synthesis of (+)-nebivolol intermediates

Devi¹,

Das²

2017

Beilstein J. Org. Chem.

View full text Add to dashboard Cite

While the exploitation of the Sharpless asymmetric dihydroxylation as the source of chirality in the synthesis of acyclic molecules and saturated heterocycles has been tremendous, its synthetic utility toward chiral benzo-annulated heterocycles is relatively limited. Thus, in the search for wider applications of Sharpless asymmetric dihydroxylation-derived diols for the synthesis of benzo-annulated heterocycles, we report herein our studies in the asymmetric synthesis of (R)-1-((R)-6-fluorochroman-2-yl)ethane-1,2-diol, (R)-1-((S)-6-fluorochroman-2-yl)ethane-1,2-diol and (S)-6-fluoro-2-((R)-oxiran-2-yl)chroman, which have been used as late-stage intermediates for the asymmetric synthesis of the antihypertensive drug (S,R,R,R)-nebivolol. Noteworthy is that a large number of racemic and asymmetric syntheses of nebivolol and their intermediates have been described in the literature, however, the Sharpless asymmetric dihydroxylation has never been employed as the sole source of chirality for this purpose.

show abstract

Novel 2,3-Dihydrobenzofuran-2-carboxylic Acids: Highly Potent and Subtype-Selective PPARα Agonists with Potent Hypolipidemic Activity

Cited by 91 publications

References 33 publications

Pharmacophore modeling and parallel screening for PPAR ligands

Pharmacophore modeling and parallel screening for PPAR ligands

Structural Insight Into the Crucial Role of Ligand Chirality in the Activation of PPARs by Crystallographic Methods

Studies directed toward the exploitation of vicinal diols in the synthesis of (+)-nebivolol intermediates

Contact Info

Product

Resources

About