Discovery of novel indazole derivatives as dual angiotensin II antagonists and partial PPARγ agonists

Lamotte, Yann; Faucher, Nicolas; Sançon, Julien; Pineau, Olivier; Sautet, Stéphane; Fouchet, Marie-Hélène; Bénéton, Véronique; Tousaint, Jean-Jacques; Saintillan, Yannick; Ancellin, Nicolas; Nicodème, Edwige; Grillot, Didier; Martres, Paul

doi:10.1016/j.bmcl.2014.01.004

Cited by 21 publications

(12 citation statements)

References 20 publications

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“…Compounds 17 and 18 (Figure 9) exert potent dual activity, AT 1 R antagonism and partial proliferator-activated receptor-γ (PPARγ) agonism and have desirable ADME properties [71,72].…”

Section: Resultsmentioning

confidence: 99%

Rational Drug Design and Synthesis of Molecules Targeting the Angiotensin II Type 1 and Type 2 Receptors

2015

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Abstract:The angiotensin II (Ang II) type 1 and type 2 receptors (AT1R and AT2R) orchestrate an array of biological processes that regulate human health. Aberrant function of these receptors triggers pathophysiological responses that can ultimately lead to death. Therefore, it is important to design and synthesize compounds that affect beneficially these two receptors. Cardiovascular disease, which is attributed to the overactivation of the vasoactive peptide hormone Αng II, can now be treated with commercial AT1R antagonists. Herein, recent achievements in rational drug design and synthesis of molecules acting on the two AT receptors are reviewed. Quantitative structure activity relationships (QSAR) and molecular modeling on the two receptors aim to assist the search for new active compounds. As AT1R and AT2R are GPCRs and drug action is localized in the transmembrane region the role of membrane bilayers is exploited. The future perspectives in this field are outlined. Tremendous progress in the field is expected if the two receptors are crystallized, as this will assist the structure based screening of the chemical space and lead to new potent therapeutic agents in cardiovascular and other diseases.

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“…Compounds 17 and 18 (Figure 9) exert potent dual activity, AT 1 R antagonism and partial proliferator-activated receptor-γ (PPARγ) agonism and have desirable ADME properties [71,72].…”

Section: Resultsmentioning

confidence: 99%

Rational Drug Design and Synthesis of Molecules Targeting the Angiotensin II Type 1 and Type 2 Receptors

2015

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“…In Zucker fa/fa rats, 15 reduced the plasma insulin and plasma triglycerides. Interestingly, no body weight gain, a typical side effect of PPARγ full agonists, was observed in comparison to vehicle control (Lamotte et al, 2014).…”

Section: Pparγ and At1mentioning

confidence: 89%

Multi-Target Approaches in Metabolic Syndrome

2021

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Metabolic syndrome (MetS) is a highly prevalent disease cluster worldwide. It requires polypharmacological treatment of the single conditions including type II diabetes, hypertension, and dyslipidemia, as well as the associated comorbidities. The complex treatment regimens with various drugs lead to drug-drug interactions and inadequate patient adherence, resulting in poor management of the disease. Multi-target approaches aim at reducing the polypharmacology and improving the efficacy. This review summarizes the medicinal chemistry efforts to develop multi-target ligands for MetS. Different combinations of pharmacological targets in context of in vivo efficacy and future perspective for multi-target drugs in MetS are discussed.

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“…11) exert potent dual activity, AT 1 R antagonism and partial proliferatoractivated receptor-γ (PPARγ) agonism and have desirable ADME properties 29,30 . …”

Section: Fig 10: Dual Calcium Channel and At1r Blockermentioning

confidence: 99%

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2017

IJPSR

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ABSTRACT:The renin-angiotensin system (RAS) plays an important role in pathogenesis of hypertension, congestive heart failure, and chronic renal failure. In addition to a discussion of the current understanding of the chemical structures and the modes of action of angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor (ATR) antagonists, review includes their SAR analysis and chemical modification for improving their activity. Nowadays different modeling strategies are underway to develop tailor made molecules with the best of properties among nonpeptide renin inhibitors, dual action receptor antagonists (e.g. angiotensin and endothelin antagonists, ACE/NEP inhibitors, AT 1 /TxA 2 antagonists, balanced AT 1 /AT 2 antagonists), triple inhibitors. In the first part is given an overview of various ACE inhibitors. The second part is devoted to overview of angiotensin receptor antagonists. The advances that have been made, new opportunities, and future directions of design and development of these classes have been discussed.

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Discovery of novel indazole derivatives as dual angiotensin II antagonists and partial PPARγ agonists

Cited by 21 publications

References 20 publications

Rational Drug Design and Synthesis of Molecules Targeting the Angiotensin II Type 1 and Type 2 Receptors

Rational Drug Design and Synthesis of Molecules Targeting the Angiotensin II Type 1 and Type 2 Receptors

Multi-Target Approaches in Metabolic Syndrome

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