Discovery and Optimization of a Novel Class of Orally Active Nonpeptidic Endothelin-A Receptor Antagonists

Riechers, Hartmut; Albrecht, Hans; Amberg, Willi; Baumann, Ernst A.; Bernard, Harald; Böhm, Hans‐Joachim; Klinge, D. E.; Kling, Andreas; Müller, Stefan; Raschack, Manfred; Unger, Liliane; Walker, Nigel; Wernet, Wolfgang

doi:10.1021/jm960274q

Cited by 115 publications

(72 citation statements)

References 22 publications

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“…The affinity of ambrisentan for human ET-receptors expressed in CHO cells was approximately 1 nM for ET A and 195 nM for ET B -receptors (65). However, in intact cell lines expressing recombinant human ET-receptors, the selectivity for the ET A -as compared to ET B receptors was 54-fold higher in CHO cells (8) (1).…”

Section: In Vitromentioning

confidence: 97%

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Ambrisentan, a Non‐peptide Endothelin Receptor Antagonist

Vatter

Seifert

2006

Cardiovascular Drug Reviews

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Increasing numbers of experimental investigations and recently also of clinical trials strongly suggest an integral involvement of the endothelin (ET)-system in the pathophysiology of a variety of disease states, mainly of the cardiovascular system. Ambrisentan (LU 208075), a selective ET A -receptor antagonist, is an orally active diphenyl propionic acid derivative. It has been shown to have a very promising efficacy to safety ratio in the initial clinical trials. Phase II and Phase III trials with ambrisentan in pulmonary arterial hypertension have been performed. The pharmacological properties and data from the experimental investigations suggest additional possible uses of ambrisentan in the prevention of reperfusion injury after organ transplantation and in restenosis following coronary artery dilatation. Furthermore, the pharmacological profile of ambrisentan indicates that this drug may also be suitable in the treatment of cerebrovascular disorders. In the present article basic investigations, animal studies and clinical trials with ambrisentan are reviewed. This review may help to define pathophysiological conditions, in which ambrisentan could be indicated and further evaluated in appropriate preclinical and clinical trials.

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Section: In Vitromentioning

confidence: 97%

“…Modification of this structure with the aim to simplify the structure and to enhance the binding activity led to a series of potent orally available ET A -selective receptor antagonists (9,65). The active enantiomer of the first compound was named LU 135252, which was studied clinically as darusentan (Fig.…”

Section: Chemistry and Development Of Ambrisentanmentioning

confidence: 99%

Ambrisentan, a Non‐peptide Endothelin Receptor Antagonist

Vatter

Seifert

2006

Cardiovascular Drug Reviews

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“…At 23 months of age, 8 animals were euthanized and kidneys removed. At 2 and 23 months, animals (9 to 10 per group) were randomized to 28 days of treatment with or without the orally active ET A receptor antagonist darusentan (LU135252; 20 mg/kg per day; Knoll AG) 16 administered in the drinking water. 17 On the day before euthanization, 24-hour metabolic studies were performed as described.…”

Section: Animal Experimentsmentioning

confidence: 99%

Role of Podocytes for Reversal of Glomerulosclerosis and Proteinuria in the Aging Kidney After Endothelin Inhibition

et al. 2004

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Abstract-The cause of focal-segmental glomerulosclerosis as a consequence of physiological aging, which is believed to be inexorable, is unknown. This study investigated whether inhibition of endothelin-1, a growth-promoting peptide contributing to renal injury in hypertension and diabetes, affects established glomerulosclerosis and proteinuria in the aged kidney. We also determined the role of endothelin receptors for podocyte injury in vivo and in vitro. Aged Wistar rats, a model of spontaneous age-dependent glomerulosclerosis, were treated with the orally active endothelin subtype A (ET A ) receptor antagonist darusentan, and evaluation of renal histology, renal function studies, and expression analyses were performed. In vitro experiments using puromycin aminonucleoside to induce podocyte injury investigated the role of ET A receptor signaling for apoptosis, cytoskeletal injury, and DNA synthesis. In aged Wistar rats, established glomerulosclerosis and proteinuria were reduced by Ͼ50% after 4 weeks of darusentan treatment, whereas blood pressure, glomerular filtration rate, or tubulo-interstitial renal injury remained unaffected. Improvement of structural injury in glomeruli and podocytes was accompanied by a reduction of the expression of matrix metalloproteinase-9 and p21 Cip1/WAF1 . In vitro experiments blocking ET A receptors using specific antagonists or RNA interference prevented apoptosis and structural damage to podocytes induced by puromycin aminonucleoside. In conclusion, these results support the hypothesis that endogenous endothelin contributes to glomerulosclerosis and proteinuria in the aging kidney. The results further suggest that age-dependent glomerulosclerosis is not merely a "degenerative" but a reversible process locally confined to the glomerulus involving recovery of podocytes from previous injury. Key Words: arterial presure Ⅲ nephrosclerosis Ⅲ DNA Ⅲ kidney failure Ⅲ renal artery Ⅲ expression Ⅲ kidney Ⅲ renal disease A ging represents an important factor determining onset and course of disease and has become a significant issue in view of the anticipated increase of the aging population. Aging in humans and rodents progressively impairs renal function 1,2 and structure, the latter of which is characterized by damage of podocytes and mesangial matrix, as well as capillary hypertrophy and obliteration resulting in glomerulosclerosis. 2 The exact mechanisms underlying agedependent renal injury are unknown. In otherwise healthy individuals Ն65 years of age, even in the absence of known risk factors such as hypertension or diabetes, glomerulosclerosis is frequently present. 3 Currently, Ϸ1.4% of the US total population is affected, and the incidence is expected to increase to Ͼ2% within the next 15 years. 3 Glomerulosclerosis and proteinuria involve injury of podocytes, also known as glomerular epithelial cells that maintain an intact filtration barrier and control glomerular basement membrane turnover under normal conditions. 4 -7 In addition to cell-specific changes during aging, cell c...

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“…,Ala 11,15 ]ET-1 [10][11][12][13][14][15][16][17][18][19][20][21] ; IRL2500, N- (3,5-dimethylbenzoyl 1,3,11,15 ]ET-1 (Molenaar et al, 1992), sarafotoxin S6c (Russell and Davenport, 1996), IRL1620 (Watakabe et al, 1992), BQ3020 (Russell and Davenport, 1996) Selective antagonists A127722 (9.2-10.5, Opgenorth et al, 1996), LU135252 (8.9, Riechers et al, 1996) (Bowery et al, 2002;Pin et al, 2004Pin et al, , 2007. The GABA B1 subunit, when expressed alone, binds both antagonists and agonists, but the affinity of the latter is generally 10-100-fold less than for the native receptor.…”

Section: Abbreviations: A127722 Trans-trans-2-(4-methoxyphenyl)-4-(1mentioning

confidence: 99%

7TM Receptors

Alexander¹,

Mathie²,

Peters³

2008

British J Pharmacology

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Overview: Alongside the 7-transmembrane receptors listed in the Guide to Receptors and Channels, IUPHAR recognises a number of genes, which sequence analysis suggests code for 7-transmembrane receptors and for which an endogenous ligand has yet to be identified (Foord et al., 2006). Below are listed a number of these genes, for which preliminary evidence for an endogenous ligand has been published. Further Reading Citation InformationWe recommend that any citations to information in the Guide are presented in the following format:Alexander SPH, . Guide to Receptors and Channels (GRAC), 3rd edn. Br J Pharmacol 153 (Suppl. 2): S1-S209. GPR1 ENSG00000183671 GPR3 ENSG00000181773 ACCA GPR4 ENSG00000177464 Proton-sensing, sphingosylphosphorylcholine GPR6 ENSG00000146360 GPR10 ENSG00000119973 GPR12 ENSG00000132975 GPCR21 GPR15 ENSG00000154165 GPR19 ENSG00000183150 GPR20 ENSG00000204882 GPR21 ENSG00000188394 GPR22 ENSG00000172209 GPR25 ENSG00000170128 GPR26 ENSG00000154478 GPR27 ENSG00000170837 SREB1 GPR31 ENSG00000120436 GPR32 ENSG00000142511 GPR33 ENSMUSG00000035148 Pseudogene in man GPR37 ENSG00000170775 PAELR, EDNRLB GPR45 ENSG00000135973 PSP24 GPR48 ENSG00000205213 Leucine-rich repeat-containing G-protein coupled receptor 4 GPR49 ENSG00000139292LGR5, GPR67, FEX, HG38 , MGC117008 GPR50 ENSG00000102195 H9 GPR52 ENSG00000203737 GPR56 ENSG00000205336 TM7LN4, TM7XN1 GPR61 ENSG00000156097 BALGR GPR62 ENSG00000180929 GPR63 ENSG00000112218 PSP24B GPR64 ENSG00000173698 HE6 GPR65 ENSG00000140030 TDAG8 GPR68 ENSG00000119714 OGR1, Proton-sensing GPR70 ENSG00000173662 TAS1R1 GPR71 ENSG00000179002 TAS1R2 GPR72 ENSG00000123901 GPR83 GPR75 ENSG00000119737 WI31133 GPR77 ENSG00000134830 C5L2 GPR78 ENSG00000155269 GPR81 ENSG00000196917 TAGPCR, GPR104 GPR82 ENSG00000171657 GPR84 ENSG00000139572 EX33 GPR85 ENSG00000164604 SREB2 GPR87 ENSG00000138271 GPR95 GPR88 ENSG00000181656 STRG GPR90 ENSMUSG00000059408 Mas-related GPR, member H GPR97 ENSG00000182885 Pb99, PGR26 GPR98 ENSG00000164199 VLGR1 GPR101 ENSG00000165370 GPR107 ENSG00000148358 KIAA1624, RP11-88G17, FLJ20998, LUSTR1 GPR110 ENSG00000153292 hGPCR36, PGR19 GPR111 ENSG00000164393 hGPCR35, PGR20 GPR112 ENSG00000156920 RP1-299I16, PGR17 GPR113 ENSG00000173567 hGPCR37, PGR23 GPR114 ENSG00000159618 PGR27 Symbol Ensembl ID Other names GPR115 ENSG00000153294 FLJ38076, PGR18 GPR116 ENSG00000069122 DKFZp564O1923, KIAA0758 GPR123 ENSG00000197177 KIAA1828 GPR124 ENSG00000020181 Tumour endothelial marker 5 GPR126 ENSG00000112414 FLJ14937 GPR127 ENSG00000186629 PGR16, EMR4 GPR128 ENSG00000144820 FLJ14454 GPR132 ENSG00000183484 G2A GPR133 ENSG00000111452 PGR25 GPR136 ENSG00000124818 OPN5, neuropsin, PGR14 GPR137 ENSG00000173264 GPR137A, TM7SF1L1 GPR139 ENSG00000180269 PGR3 GPR140 ENSG00000172935MRGPRF, GPR168, RTA GPR141 ENSG00000187037 PGR13 GPR142 ENSG00000196169 PGR2, KIF19 GPR143 ENSG00000101850 OA1 GPR144 ENSG00000180264 PGR24 GPR146 ENSG0000016...

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Discovery and Optimization of a Novel Class of Orally Active Nonpeptidic Endothelin-A Receptor Antagonists

Cited by 115 publications

References 22 publications

Ambrisentan, a Non‐peptide Endothelin Receptor Antagonist

Ambrisentan, a Non‐peptide Endothelin Receptor Antagonist

Role of Podocytes for Reversal of Glomerulosclerosis and Proteinuria in the Aging Kidney After Endothelin Inhibition

7TM Receptors

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