Discovery of a Potent, Orally Bioavailable β3 Adrenergic Receptor Agonist, (R)-N-[4-[2-[[2-Hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[4-[4-(trifluoromethyl)phenyl]thiazol-2-yl]benzenesulfonamide

Rj, Mathvink; Js, Tolman; Chitty, Dawn; Mr, Candelore; Ma, Cascieri; Lf, Colwell; Deng, Liping; Wp, Feeney; Mj, Forrest; Gj, Hom; De, MacIntyre; Rr, Miller; Ra, Stearns; Tota, Laurie; Mj, Wyvratt; Mh, Fisher; Ae, Weber

doi:10.1021/jm000286i

Cited by 63 publications

(25 citation statements)

References 15 publications

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“…Furthermore, experiments with hepatectomy and hepatic warm ischemia/reperfusion injury demonstrated that IL-6 is a critical component for hepatocyte proliferation and liver regeneration (Camargo et al, 1997; Cressman et al, 1996). In pursuit of novel therapeutic approaches a series of human β 3 AR agonists and antagonists has recently been generated (Brockunier et al, 2001; Candelore et al, 1999; Mathvink et al, 2000; Parmee et al, 2000). Thus, this work may promote the development of new therapeutic avenues for the treatment of obesity, inflammatory pain conditions, brain pathology, and liver diseases.…”

Section: Discussionmentioning

confidence: 99%

Signaling pathways mediating β3-adrenergic receptor-induced production of interleukin-6 in adipocytes

Tchivileva

Tan

Gambarian

et al. 2009

Molecular Immunology

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The β 3 -adrenergic receptor (β 3 AR) is an essential regulator of metabolic and endocrine functions. A major cellular and clinically significant consequence of β 3 AR activation is the substantial elevation in interleukin-6 (IL-6) levels. Although the β 3 AR-dependent regulation of IL-6 expression is well established, the cellular pathways underlying this regulation have not been characterized. Using a novel method of homogenous reporters, we assessed the pattern of activation of 43 transcription factors in response to the specific β 3 AR agonist CL316243 in adipocytes, cells that exhibit the highest expression of β 3 ARs. We observed a unique and robust activation of the CRE-response element, suggesting that IL-6 transcription is regulated via the G s -protein/cAMP/protein kinase A (PKA) but not nuclear factor kappa B (NF-κB) pathway. However, pretreatment of adipocytes with pharmacologic inhibitors of PKA pathway failed to block β 3 AR-mediated IL-6 up-regulation. Additionally, stimulation of adipocytes with the exchange protein directly activated by cAMP (Epac) agonist did not induce IL-6 expression. Instead, the β 3 AR-mediated transcription of IL-6 required activation of both the p38 and PKC pathways. Western blot analysis further showed that transcription factors CREB and ATF-2 but not ATF-1 were activated in a p38-and PKC-dependent manner. Collectively, our results suggest that while stimulation of the β 3 AR leads to a specific activation of CRE-dependent transcription, there are several independent cellular pathways that converge at the level of CRE-response element activation, and in the case of IL-6 this activation is mediated by p38 and PKC but not PKA pathways.

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Section: Discussionmentioning

confidence: 99%

Signaling pathways mediating β3-adrenergic receptor-induced production of interleukin-6 in adipocytes

Tchivileva

Tan

Gambarian

et al. 2009

Molecular Immunology

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“…Researchers at Merck explored a series of benzenesulfonamide β 3 -agonists and identified potent, selective and orally bioavailable compounds [17][18][19][20][21][22][23][24][25][26]. A hexylurea derivative 4 (L-757,793) was found to be a potent agonist of human β 3 -AR (EC 50 = 6.3 nM) with high selectivity over β 1 -and β 2 -ARs (>1000-folds) [17].…”

Section: Modification Of Rhsmentioning

confidence: 99%

Subject Index to Volume 12

Sawa

Harada²

2006

curr med chem

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The beta3-adrenergic receptor (beta3-AR) has been shown to mediate various pharmacological and physiological effects such as lipolysis, thermogenesis, and relaxation of the urinary bladder. Activation of the beta3-AR is thought to be a possible approach for the treatment of obesity, type 2 diabetes mellitus, and frequent urination. Therefore, the beta3-AR is recognized as an attractive target for drug discovery. On the other hand, activation of the beta1- or beta2-AR can cause undesirable side effects such as increased heart rate or muscle tremors. Consequently, a number of recent efforts in this field have been directed toward the design of selective agonists for the beta3-AR. This review summarizes recent advances in beta3-AR agonists with an emphasis on recent attempts to create potent, selective and orally bioavailable small-molecule agonists.

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“…In recent years, the activation of human b 3 -adrenergic receptor (b 3 -AR) has attracted much attention [1][2][3][4][5][6][7][8][9][10][11][12][13] as a potential approach towards the treatment of obesity [14-20] and non-insulin dependent diabetes mellitus (NIDDM) [19][20][21], which is increasing at an alarming rate in western countries. The b 3 -AR, which was initially (1980s) referred as atypical because of the characterization of only b 1 -and b 2 -AR at that time, also belongs to the seven transmembrane G-protein coupled receptor, present in white and brown adipose tissues [22], gastrointestinal tract [23], stomach [23] and some heart tissues [24].…”

Section: Introductionmentioning

confidence: 99%

Characterization of β3-adrenergic receptor: determination of pharmacophore and 3D QSAR model for β3 adrenergic receptor agonism

Prathipati

Saxena

2005

J Comput Aided Mol Des

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The beta3-adrenoreceptor (beta3-AR) has been shown to mediate various pharmacological and physiological effects such as lipolysis, thermogenesis, and intestinal smooth muscle relaxation. It also plays an important role in glucose homeostasis and energy balance. Molecular modeling studies were undertaken to develop predictive pharmacophoric hypothesis and 3D-QSAR model, which may explain variations in beta3-AR agonistic activity in terms of chemical features and physicochemical properties. The two softwares, CATALYST for pharmacophoric alignment and APEX-3D for 3D-QSAR modeling were used to establish the structure activity relationships for beta3-AR agonistic activity. Among the several statistically significant models, the selection of the best pharmacophore and 3D-QSAR model was based on its ability to estimate the activity of external test sets of similar and different structural types along with the reasonable consistency of the model with the limited information of the active site of beta3-AR. The final 3D-QSAR model was derived using the pharmacophoric alignments from the hypothesis which consisted of four chemical features: basic or positive ionizable feature on the nitrogen of the aryloxypropylamino group, two ring aromatic features corresponding to the phenyl ring of the phenoxide and the benzenesulphonamido groups and a hydrogen-bond donor (HBD) in the vicinity of the nitrogen atom of the benzenesulphonamido group with the most active molecule mapping in an energetically favorable extended conformation. This hypothesis was in agreement with the site directed mutagenesis studies on human beta3-AR and correlated well the observed and estimated activity both in, training and both the external test sets. It also mapped reasonably well to six beta3-AR agonists of different structural classes under clinical development and thus this hypothesis may have a universal applicability in providing a powerful template for virtual screening and also for designing new chemical entities (NCEs) as beta3-AR agonists.

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Discovery of a Potent, Orally Bioavailable β₃ Adrenergic Receptor Agonist, (R)-N-[4-[2-[[2-Hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[4-[4-(trifluoromethyl)phenyl]thiazol-2-yl]benzenesulfonamide

Cited by 63 publications

References 15 publications

Signaling pathways mediating β3-adrenergic receptor-induced production of interleukin-6 in adipocytes

Signaling pathways mediating β3-adrenergic receptor-induced production of interleukin-6 in adipocytes

Subject Index to Volume 12

Characterization of β3-adrenergic receptor: determination of pharmacophore and 3D QSAR model for β3 adrenergic receptor agonism

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