(4-Piperidin-1-yl)phenyl Amides:  Potent and Selective Human β<sub>3</sub> Agonists

Hu, Baihua; Ellingboe, John W.; Han, Stella; Largis, Elwood; Mulvey, Ruth; Oliphant, Alexander; Sum, Fuk‐Wah; Tillett, Jeff

doi:10.1021/jm000544b

Cited by 22 publications

(11 citation statements)

References 14 publications

(19 reference statements)

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“…10-fold) activity at the human b 3 -AR and enhanced selectivity at both the b 1 -and b 2 -ARs. This result is consistent with published data from earlier SARs [62][63][64][65] studies indicating that carboxylic acids are usually more selective than the corresponding esters. On the other hand, 50, which lacks substituent on the RHS of the indole nucleus, displayed the most potent b 1 -AR agonistic activity with a modest human b 3 -AR agonistic activity.…”

Section: Brl 37344supporting

confidence: 93%

Discovery of a Novel and Potent Human and Rat .BETA.3-Adrenergic Receptor Agonist, [3-[(2R)-[[(2R)-(3-Chlorophenyl)-2-hydroxyethyl]amino]propyl]-1H-indol-7-yloxy]acetic Acid

Harada

Hirokawa

Suzuki

et al. 2005

CHEMICAL & PHARMACEUTICAL BULLETIN

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1) This sub-classification has led to the development of b 1 -and b 2 -AR antagonists and/or agonists which have been useful for the treatment of cardiovascular diseases and asthma. In early 1980s, a third b-AR, initially referred to as "atypical"2) and later called b 3 -AR has been found in a number of species, including man, [3][4][5][6] and in 1989, the human, 7) rat, 8) and mouse 9) b 3 -ARs were first cloned and characterized. Like other b-ARs, b 3 -ARs belong to the G-protein-coupled receptor family that includes receptors with a common structure consisting of seven transmembrance-spanning connected by interhelical loops.10) The b 3 -AR is located on the surface of both white and brown adipocytes and is known to be stimulated by endogenous catecholamines, adrenalin, and noradrenaline. It has also been reported that b 3 -AR receptor plays a significant role in regulating lipolysis and thermogenesis in rodent and human adipose tissues. 11,12) Moreover, studies of b 3 -AR mRNA demonstrated that, b 3 -ARs exist in human heart, gall bladder, gastrointestinal tract, prostate, and urinary bladder detrusor tissue in addition to adipocytes. [13][14][15][16] Since the discovery of b 3 -AR, a number of laboratories have been engaged in developing potent and selective b 3 -AR agonists for the treatment of various metabolic and gastrointestinal diseases such as obesity, non-insulin dependent (Type-II) diabetes, irritable bowel syndrome, and urinary frequency and incontinence. [17][18][19][20][21] Early b 3 -AR agonists (the "first generation" of potent and selective rat b 3 -AR agonists) such as BRL 37344 (BRL 35135), [22][23][24] CL 316243, [25][26][27] and SR 58611A, 28) having a 3-chlorophenyl moiety in the left-hand side (LHS) and a carboxylic acid or an ester functionality in the right-hand side (RHS) as shown in Chart 1, have been reported to be effective anti-obesity and anti-diabetic agents in rodents.29) These compounds, through their potent agonistic activity for the b 3 -AR, stimulate lipolysis and energy expenditure and cause only a slight increase in heart rate (b 1 -AR activity) and weak muscle tremor (b 2 -AR activity). Unfortunately, some of these early b 3 -AR agonists developed for the treatment of metabolic disorders failed to produce similar effects in humans, due to a lack of selectivity and/or potency, or poor pharmacokinetics.30) Because of structural differences between human and rat b 3 -ARs with regard to the amino acid sequences of each receptor, activity at the rat b 3 -AR could not effectively predict that at the human b 3 -AR.31) Thus, a new generation of human b 3 -AR agonists with minimal side effects associated with activation of human b 1 -and b 2 -ARs has long been needed.A new generation of b 3 -AR agonists currently under preclinical development is represented by the tetrahydroisoquinoline 1, [32][33][34] SB 226552, 35,36) L 755507, 37) L 770644, 38,39) and LY-377604 40) (Chart 1). These compounds having both potent and full agonistic activity, and high selectivity at the human b...

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Section: Brl 37344supporting

confidence: 93%

Discovery of a Novel and Potent Human and Rat .BETA.3-Adrenergic Receptor Agonist, [3-[(2R)-[[(2R)-(3-Chlorophenyl)-2-hydroxyethyl]amino]propyl]-1H-indol-7-yloxy]acetic Acid

Harada

Hirokawa

Suzuki

et al. 2005

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…L755507 is a potent agonist at the human ␤ 3 -AR, with 440-fold selectivity for ␤ 3 -AR compared with ␤ 1 or ␤ 2 -ARs (Parmee et al, 1998). It elevates at ASPET Journals on May 9, 2018 molpharm.aspetjournals.org cAMP in CHOh␤ 3 cells, causes thermogenesis in transgenic mice expressing human ␤ 3 -ARs (Hu et al, 2001), and induces lipolysis and an elevation of metabolic rate in rhesus monkeys .…”

mentioning

confidence: 99%

The β₃-Adrenoceptor Agonist 4-[[(Hexylamino)carbonyl]amino]-N-[4-[2-[[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino]ethyl]-phenyl]-benzenesulfonamide (L755507) and Antagonist (S)-N-[4-[2-[[3-[3-(Acetamidomethyl)phenoxy]-2-hydroxypropyl]amino]-ethyl]phenyl]benzenesulfonamide (L748337) Activate Different Signaling Pathways in Chinese Hamster Ovary-K1 Cells Stably Expressing the Human β₃-Adrenoceptor

Sato

Hutchinson²,

Evans³

et al. 2008

Mol Pharmacol

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This study identifies signaling pathways activated by the ␤ 2 -/␤ 3 -adrenoceptor (AR) agonist zinterol, the selective ␤ 3 -AR agonist L755507, and the selective ␤ 3 -AR antagonist L748337 in CHO-K1 cells expressing human ␤ 3 -adrenoceptors. Zinterol and L755507 caused a robust concentration-dependent increase in cAMP accumulation (pEC 50 values of 8.5 and 12.3, respectively), whereas L748337 had low efficacy. Maximal cAMP accumulation with zinterol and L755507 was increased after pretreatment with pertussis toxin, indicating that the human ␤ 3 -AR couples to G i and to G s . In contrast to cAMP, zinterol, L755507 and L748337 increased phosphorylation of extracellular signal-regulated kinase 1/2 (Erk1/2) with very high potency (pEC 50 values of 10.9, 11.7, and 11.6). These compounds also stimulated phosphorylation of p38 mitogen-activated protein kinase (MAPK) but with much lower potency than Erk1/2 (pEC 50 values of 5.9, 5.5, and 5.7, respectively). Pertussis toxin completely blocked Erk1/2 and p38 MAPK phosphorylation in response to L748337, demonstrating a requirement for G i/o coupling, whereas L755507-stimulated p38 MAPK phosphorylation was not inhibited by pertussis toxin, and Erk1/2 phosphorylation was inhibited by only 30%. We found that high levels of cAMP interfered with agonist-activated p38 MAPK phosphorylation. L748337 increased extracellular acidification rate (ECAR) in the cytosensor microphysiometer with efficacy similar to zinterol and L755507, albeit with lower potency (pEC 50 value of 7.2 compared with zinterol, 8.1, and L755507, 8.6). The ECAR response to L748337 was largely via activation of p38 MAPK, demonstrated by 65% inhibition with 4-[4-(4-fluorophenyl)-1-(3-phenylpropyl)-5-(4-pyridinyl)-1H-imidazol-2-yl]-3-butyn-1-ol (RWJ67657). We conclude that the ␤ 3 -AR agonist L755507 couples to both G s and G i to activate adenylate cyclase and MAPK signaling, whereas the ␤ 3 -AR antagonist L748337 couples predominantly to G i to activate MAPK signaling.␤-Adrenoceptors (ARs) mediate responses to circulating adrenaline and to noradrenaline released from sympathetic nerve terminals. The ␤ 1 -, ␤ 2 -, and ␤ 3 -AR subtypes have distinct patterns of expression in heart, lung, blood vessels, the gastrointestinal tract, adipose tissue, and the central ner-

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“…On the other hand, activation of the b 1 -AR or b 2 -AR would lead to produce undesirable side effects such as muscle tremors and increased heart rate. Current research in this area is mainly focused on developing selective agonists of b 3 -AR for producing antiobesity as well as antidiabetic effects (Ok et al, 2000;Hu et al, 2001;Parmee et al, 1998;Dow et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Three-dimensional QSAR and pharmacophore mapping of biphenyl benzoic acid derivatives as selective human β3-adrenergic receptor agonists

et al. 2009

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Molecular modeling studies were performed to develop a predictive common pharmacophore hypothesis (CPH) and use it for alignment in threedimensional (3D) quantitative structure-activity relationship (QSAR) studies using CoMFA and CoMSIA, with a diverse set of 80 b 3 -adrenergic receptor (b 3 -AR) agonists. Using PHASE (Pharmacophore Alignment and Scoring Engine) six-point CPH with one acceptor, one negative charge, one positive charge, and three rings, features were derived for pharmacophore-based alignment of molecules. CPH was selected by correlating the observed and estimated activity for the training set and test set of molecules using partial least squares analysis. The validated pharmacophore hypothesis was used for alignment of molecules in CoMFA and CoMSIA model development. The models so generated showed a good ''predictive'' r 2 value of 0.6635 and 0.8665 for CoMFA and CoMSIA, respectively. The 3D contour CoMFA/CoMSIA maps provided an interpretable explanation of SAR for the compounds and also permitted interesting conclusions about the substituent effects at different positions of the biphenyl benzoic acid derivatives. CPH can also provide a powerful template for virtual screening and design of new b 3 -AR agonists.

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(4-Piperidin-1-yl)phenyl Amides: Potent and Selective Human β₃ Agonists

Cited by 22 publications

References 14 publications

Discovery of a Novel and Potent Human and Rat .BETA.3-Adrenergic Receptor Agonist, [3-[(2R)-[[(2R)-(3-Chlorophenyl)-2-hydroxyethyl]amino]propyl]-1H-indol-7-yloxy]acetic Acid

Discovery of a Novel and Potent Human and Rat .BETA.3-Adrenergic Receptor Agonist, [3-[(2R)-[[(2R)-(3-Chlorophenyl)-2-hydroxyethyl]amino]propyl]-1H-indol-7-yloxy]acetic Acid

Three-dimensional QSAR and pharmacophore mapping of biphenyl benzoic acid derivatives as selective human β3-adrenergic receptor agonists

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(4-Piperidin-1-yl)phenyl Amides: Potent and Selective Human β3 Agonists

Cited by 22 publications

References 14 publications

Discovery of a Novel and Potent Human and Rat .BETA.3-Adrenergic Receptor Agonist, [3-[(2R)-[[(2R)-(3-Chlorophenyl)-2-hydroxyethyl]amino]propyl]-1H-indol-7-yloxy]acetic Acid

Discovery of a Novel and Potent Human and Rat .BETA.3-Adrenergic Receptor Agonist, [3-[(2R)-[[(2R)-(3-Chlorophenyl)-2-hydroxyethyl]amino]propyl]-1H-indol-7-yloxy]acetic Acid

Three-dimensional QSAR and pharmacophore mapping of biphenyl benzoic acid derivatives as selective human β3-adrenergic receptor agonists

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(4-Piperidin-1-yl)phenyl Amides: Potent and Selective Human β₃ Agonists