Selective Angiotensin II AT<sub>2</sub> Receptor Agonists:  Arylbenzylimidazole Structure−Activity Relationships

Wu, Xiongyu; Wan, Yiqian; Arulprakasajothi, M.; Murugaiah, A. M. S.; Plouffe, Bianca; Botros, Milad; Karlén, Anders; Hallberg, Mathias; Gallo‐Payet, Nicole; Alterman, Mathias

doi:10.1021/jm0606185

Cited by 46 publications

(48 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1−3 In 2004, the first selective and drug-like AT 2 receptor agonist C21/ M024 (1) was disclosed, 4 and thereafter, a series of structural analogues with agonistic properties have been reported. 5,6 The activation of the AT 2 receptor is known to render a large number of diverse biological responses. 7,8 For example, receptor activation stimulates neurite outgrowth in neuronal cells, which is one of the first steps in neuronal differentiation.…”

Section: Abstract: At 2 Receptor Nonpeptide Ligands Agonist Antagomentioning

confidence: 99%

“…This is also verified by compound 3, which previously has been tested for AT 1 receptor affinity (K i > 10 000 nM). 5 All compounds were evaluated for functionality in a neurite outgrowth assay with NG108-15 cells. The NG108-15 cells express mainly the AT 2 receptor in their undifferentiated state, and a three-day treatment with Ang II or the selective peptidic AT 2 receptor agonist CGP-42112 (N α -nicotinoyl-Tyr-(N α -CbzArg)-Lys-His-Pro-Ile) 23,24 induce neurite outgrowth.…”

Section: Acs Medicinal Chemistry Lettersmentioning

confidence: 99%

“…5,6 The activation of the AT 2 receptor is known to render a large number of diverse biological responses. 7,8 For example, receptor activation stimulates neurite outgrowth in neuronal cells, which is one of the first steps in neuronal differentiation.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Interconversion of Functional Activity by Minor Structural Alterations in Nonpeptide AT₂ Receptor Ligands

Wallinder

Sköld

Botros

et al. 2014

ACS Med. Chem. Lett.

Self Cite

View full text Add to dashboard Cite

Migration of the methylene imidazole side chain in the first reported selective drug-like AT 2 receptor agonist C21/M024 (1) delivered the AT 2 receptor antagonist C38/M132 (2). We now report that the AT 2 receptor antagonist compound 4, a biphenyl derivative that is structurally related to 2, is transformed to the agonist 6 by migration of the isobutyl group. The importance of the relative position of the methylene imidazole and the isobutyl substituent is highlighted herein. KEYWORDS:AT 2 receptor, nonpeptide ligands, agonist, antagonist, C21/M024, C38/M132 T he sartans (angiotensin II receptor blockers, ABRs) have been on the market as antihypertensives for more than two decades and act as selective antagonists at the angiotensin II AT 1 receptor. More recently, the angiotensin AT 2 receptor has emerged as a new target for drug intervention.1−3 In 2004, the first selective and drug-like AT 2 receptor agonist C21/ M024 (1) was disclosed, 4 and thereafter, a series of structural analogues with agonistic properties have been reported. 5,6 The activation of the AT 2 receptor is known to render a large number of diverse biological responses. 7,8 For example, receptor activation stimulates neurite outgrowth in neuronal cells, which is one of the first steps in neuronal differentiation. 9In healthy adults the AT 2 receptor expression is low and mainly found in renal, cardiovascular, and brain tissues. 7,8 Notably, during certain pathological conditions, such as myocardial infarction, vascular injury, brain ischemia, renal failure, and cutaneous wounds, the AT 2 receptor expression is significantly up-regulated. 7,8 Recently, several studies conducted in experimental disease models have revealed that the selective potent AT 2 receptor agonist 1 acts as an anti-inflammatory agent and exerts pronounced tissue protective effects in particular in cardiovascular and renal disease. Hence, the compound has had a large impact on the view of the AT 2 receptor as a drug target.1,9−14 In addition, the AT 2 receptor is a promising drug target for antagonists. Thus, the AT 2 receptor antagonist EMA401 has demonstrated convincing efficacy data in patients suffering from neuropathic pain (postherpetic neuralgia) in a phase II study. 3 We discovered that migration of the methylene imidazole substituent of 1 from the para to the meta substitution pattern delivered a selective AT 2 receptor antagonist, compound C38/M132 (2) (Figure 1). 15,16 Thus, a minor structural alteration resulted in the interconversion of a selective AT 2 receptor agonist to a selective AT 2 receptor antagonist.Herein, we report the synthesis and biological evaluation of four AT 2 receptor ligands, the biphenyl derivatives, and regioisomers, 3, 4, 5, and 6 (Figure 2), and that the relative position of the imidazole and isobutyl substituent determines the functional outcome.The

show abstract

Section: Abstract: At 2 Receptor Nonpeptide Ligands Agonist Antagomentioning

confidence: 99%

Section: Acs Medicinal Chemistry Lettersmentioning

confidence: 99%

See 1 more Smart Citation

Interconversion of Functional Activity by Minor Structural Alterations in Nonpeptide AT₂ Receptor Ligands

Wallinder

Sköld

Botros

et al. 2014

ACS Med. Chem. Lett.

Self Cite

View full text Add to dashboard Cite

show abstract

“…The substitution of the thienyl-phenyl to the biphenyl scaffold (resembling L162.782, Fig. 12) produced the equipotent C showing that the two scaffolds are bioisosteric in these compounds 43 . Compound D, a derivative of L162.782, was synthesized by Liu et al, in an attempt to develop new AT 2 R agonists as novel antihypertensive candidates.…”

Section: Fig 11: the Compounds With Dual At 1 R Antagonism And Pparγmentioning

confidence: 99%

Untitled

2017

IJPSR

View full text Add to dashboard Cite

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.

show abstract

“…We have also shown that 0968 the unsubstituted imidazole could be combined with substituents other than iso-butyl in the 5-postion of the thiophene. 20 Furthermore, we have shown that compounds where the thiophene has been exchanged with a phenyl maintain affinity and selectivity towards the AT 2 receptor. 20 Although the imidazole provided an excellent moiety for high affinity and selectivity towards the AT 2 receptor, it is known from literature that benzylic imidazoles frequently possess CYP 450 inhibition.…”

Section: Introductionmentioning

confidence: 97%

Selective angiotensin II AT2 receptor agonists with reduced CYP 450 inhibition

Arulprakasajothi¹,

Wan²,

Murugaiah³

et al. 2010

Bioorganic & Medicinal Chemistry

Self Cite

View full text Add to dashboard Cite

Selective Angiotensin II AT₂ Receptor Agonists: Arylbenzylimidazole Structure−Activity Relationships

Cited by 46 publications

References 31 publications

Interconversion of Functional Activity by Minor Structural Alterations in Nonpeptide AT₂ Receptor Ligands

Interconversion of Functional Activity by Minor Structural Alterations in Nonpeptide AT₂ Receptor Ligands

Untitled

Selective angiotensin II AT2 receptor agonists with reduced CYP 450 inhibition

Contact Info

Product

Resources

About

Selective Angiotensin II AT2 Receptor Agonists: Arylbenzylimidazole Structure−Activity Relationships

Cited by 46 publications

References 31 publications

Interconversion of Functional Activity by Minor Structural Alterations in Nonpeptide AT2 Receptor Ligands

Interconversion of Functional Activity by Minor Structural Alterations in Nonpeptide AT2 Receptor Ligands

Untitled

Selective angiotensin II AT2 receptor agonists with reduced CYP 450 inhibition

Contact Info

Product

Resources

About

Selective Angiotensin II AT₂ Receptor Agonists: Arylbenzylimidazole Structure−Activity Relationships

Interconversion of Functional Activity by Minor Structural Alterations in Nonpeptide AT₂ Receptor Ligands

Interconversion of Functional Activity by Minor Structural Alterations in Nonpeptide AT₂ Receptor Ligands