Synthesis and evaluation of novel phenoxypropanolamine derivatives containing acetanilides as potent and selective β3-adrenergic receptor agonists

Maruyama, Tatsuya; Onda, Kenichi; Hayakawa, Masahiko; Seki, Norio; Takahashi, Takumi; Moritomo, Hiroyuki; Suzuki, Takayuki; Matsui, Tetsuo; Takasu, Toshiyuki; Nagase, Itsuro; Ohta, Mitsuaki

doi:10.1016/j.bmc.2009.03.044

Cited by 8 publications

(6 citation statements)

References 12 publications

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“…Next, the introduction of a methyl group at the α-position of the secondary amine on the central part of 4g was investigated, since it was reported to improve β3-AR agonistic activity in phenoxypropanolamine analogue 21) (Table 3). One diastereomer of the α-methyl derivative (9a) showed a 3-fold increase in potency at the β3-AR (EC 50 =0.21 µM, IA=0.84) relative to that of 4g, however, its functional selectivity over β1-AR was decreased.…”

Section: Resultsmentioning

confidence: 99%

“…Compounds 9a and b and 11 were synthesized, as illustrated in Chart 3. Aniline intermediates 7a and b 21) were coupled with (2-phenylaminothiazol-4-yl) acetic acid, followed by cleavage of the Boc protecting group to afford the desired products 9a and b. Meanwhile, treatment of 2 with (2-methylphenylaminothiazol-4-yl) acetic acid, 22) followed by deprotection with Boc group, afforded the desired product 11.…”

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confidence: 99%

“…Treatment of aniline intermediate 2 21) with the appropriate (2-aminothiazol-4-yl) acetic acids in the presence of 1-ethyl-3-(3′-dimethylaminopropyl) carbodiimide hydrochloride, followed by deprotection of the tert-butoxycarbonyl (Boc) group with hydrochloric acid, afforded the desired products 4a-m. N-Phenyl-(2-phenylaminothiazol-4-yl) acetamides 6a-m were also prepared from aniline intermediate 2 in the same manner as 4 (Chart 2). Compounds 9a and b and 11 were synthesized, as illustrated in Chart 3.…”

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Synthesis and Evaluation of <i>N</i>-Phenyl-(2-aminothiazol-4-yl)acetamides with Phenoxypropanolamine Moiety as Selective β3-Adrenergic Receptor Agonists

Maruyama

Onda

Suzuki

et al. 2012

CHEMICAL & PHARMACEUTICAL BULLETIN

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In the search for potent and selective human β3-adrenergic receptor (AR) agonists as potential drugs for use in treating obesity and non-insulin dependent (type 2) diabetes, a series of N-phenyl-(2-aminothiazol-4-yl)acetamides with phenoxypropanolamine moiety were prepared and their biological activities against human β3-, β2-, and β1-ARs were evaluated. Among these compounds, N-phenyl-(2-phenylaminothiazol-4-yl) acetamide (4g), N-phenyl-(2-benzylaminothiazol-4-yl)acetamide (4j), and N-phenyl-[2-(3-methoxyphenyl)-aminothiazol-4-yl]acetamide (6g) derivatives showed potent agonistic activity against the β3-AR with functional selectivity over the β1-and β2-ARs. In addition, these compounds exhibited significant hypoglycemic activity in a rodent model of diabetes.Key words β3-adrenergic receptor; agonist; 2-aminothiazole; phenoxypropanolamine; diabetes A major increase in the prevalence of obesity, non-insulin dependent (type 2) diabetes and related cardiovascular disorders has led to the search for new pharmacological approaches in the treatment of these conditions. 1,2) In the 1980s and 1990s, the β3-adrenergic receptor (AR) was identified as a possible therapeutic target for the treatment of type 2 diabetes and obesity.3,4) Early potent and selective β3-AR agonists, such as BRL- 37344 5) and CL-316243, 6) were reported to be effective anti-obesity and anti-diabetic agents in rodents 7) ( Fig. 1). Human clinical trials with these agents for use in treating metabolic disorders, however, have been disappointing due to a lack of efficacy or an unfavorable side-effect profile. 8,9) The clinical failure of such compounds has been attributed to a lack of sufficient β3-AR potency and selectivity relative to β1-and β2-ARs resulting from pharmacologic differences between rodent and human receptors, a notion supported by the discovery, cloning, and characterization of the human, rat, and mouse β3-ARs. [10][11][12] Recent studies have indicated that, in addition to adipocytes, the β3-AR is also distributed in human urinary bladder detrusor tissue and its relaxation occurs mainly via β3-AR. [13][14][15] (Fig. 1). The availability of appropriate human receptors has facilitated the design and synthesis of a new generation of highly potent β3-AR agonists. Subtype selectivity for β3-AR agonists must be kept specifically in mind, since activation of the β1-or β2-ARs could lead to undesirable side effects such as increased heart rate or muscle tremors.We previously described efforts in this area that included the disclosure of acetanilide-based phenylethanolamine 1, which showed potent β3-AR agonistic activity with functional selectivity over β1-and β2-ARs and oral hypoglycemic activity in diabetic kk mice. 20) Given our assumption that the (2-aminothiazol-4-yl) acetamide moiety of 1 might be a favorable pharmaocophore for β3-AR agonistic activity and selectivity, we decided to apply this structure part in the phenoxypropanolamine analogue instead of the phenylethanolamine one. We therefore synthesized simple N-phenyl-(2-aminot...

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confidence: 99%

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Synthesis and Evaluation of <i>N</i>-Phenyl-(2-aminothiazol-4-yl)acetamides with Phenoxypropanolamine Moiety as Selective β3-Adrenergic Receptor Agonists

Maruyama

Onda

Suzuki

et al. 2012

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…CoMFA and CoMSIA studies were performed on a set of 41 phenoxypropanolamine derivatives reported by Astellas Pharma [ 29 , 30 ] ( Table 6 ). The derivatives displayed potent agonistic activity at the β3-AR.…”

Section: Methodsmentioning

confidence: 99%

“…Since then, there have been no reports of QSAR studies on aryloxypropanolamines. In the present work, we present a three-dimensional (3D)-QSAR study of a series of potent and selective human β3-AR agonists [ 29 , 30 ]. The reported compounds showed an interesting profile as potential drugs for the treatment of obesity and noninsulin-dependent (type II) diabetes.…”

Section: Introductionmentioning

confidence: 99%

Structure-Activity Relationships Based on 3D-QSAR CoMFA/CoMSIA and Design of Aryloxypropanol-Amine Agonists with Selectivity for the Human β3-Adrenergic Receptor and Anti-Obesity and Anti-Diabetic Profiles

et al. 2018

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The wide tissue distribution of the adrenergic β3 receptor makes it a potential target for the treatment of multiple pathologies such as diabetes, obesity, depression, overactive bladder (OAB), and cancer. Currently, there is only one drug on the market, mirabegron, approved for the treatment of OAB. In the present study, we have carried out an extensive structure-activity relationship analysis of a series of 41 aryloxypropanolamine compounds based on three-dimensional quantitative structure-activity relationship (3D-QSAR) techniques. This is the first combined comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) study in a series of selective aryloxypropanolamines displaying anti-diabetes and anti-obesity pharmacological profiles. The best CoMFA and CoMSIA models presented values of r2ncv = 0.993 and 0.984 and values of r2test = 0.865 and 0.918, respectively. The results obtained were subjected to extensive external validation (q2, r2, r2m, etc.) and a final series of compounds was designed and their biological activity was predicted (best pEC50 = 8.561).

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Insights into the binding modes of human β3-adrenergic receptor agonists with ligand-based and receptor-based methods

et al. 2011

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Agonists of β(3)-adrenergic receptor (AR) have been thought as potential drugs for the treatment of obesity, type II diabetes, and overactive bladder. In order to clarify the essential structure-activity relationship and the detailed binding modes of β(3)-AR agonists as well as to identify new lead compounds activating β(3)-AR, ligand-based and receptor-based methods were applied. The pharmacophore models were developed based on 144 β(3)-AR agonists. Meanwhile, the homology model of the β(3)-AR was built based on the crystal structure of β(2)-AR. The pharmacophore model and the homology model mapped with each other very well, and some important information was obtained from the docking result. For example, agonists formed similar hydrogen-bonding interactions with residues Asp117, Arg315, and Asn332, π-π stacking interaction with residues Phe308, and hydrophobic interactions with residues Val118, Val121, Ala197, Phe198, Ala199, Phe309, and Phe328 of β(3)-AR. And the major difference about binding mode from the crystal structures of β(1)- and β(2)-ARs is the hydrogen-bonding interaction with the residue Arg315, which corresponds to the residue Asn313 of β(1)-AR and the residue His296 of β(2)-AR, respectively. Our findings may be crucial for the design and development of novel selective and potent β(3)-AR agonists.

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Synthesis and evaluation of novel phenoxypropanolamine derivatives containing acetanilides as potent and selective β3-adrenergic receptor agonists

Cited by 8 publications

References 12 publications

Synthesis and Evaluation of <i>N</i>-Phenyl-(2-aminothiazol-4-yl)acetamides with Phenoxypropanolamine Moiety as Selective β3-Adrenergic Receptor Agonists

Synthesis and Evaluation of <i>N</i>-Phenyl-(2-aminothiazol-4-yl)acetamides with Phenoxypropanolamine Moiety as Selective β3-Adrenergic Receptor Agonists

Structure-Activity Relationships Based on 3D-QSAR CoMFA/CoMSIA and Design of Aryloxypropanol-Amine Agonists with Selectivity for the Human β3-Adrenergic Receptor and Anti-Obesity and Anti-Diabetic Profiles

Insights into the binding modes of human β3-adrenergic receptor agonists with ligand-based and receptor-based methods

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