Tryptamine-based human β3-adrenergic receptor agonists. Part 3: Improved oral bioavailability via modification of the sulfonamide moiety

Sawa, Masaaki; Mizuno, Kiyonori; Harada, Hiroshi; Tateishi, Hirotaka; Arai, Yukiyo; Suzuki, Shinya; Oue, Mayumi; Tsujiuchi, Hiroshi; Furutani, Yasuji; Kato, Shiro

doi:10.1016/j.bmcl.2004.12.033

Cited by 13 publications

(9 citation statements)

References 7 publications

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“…Methods for improving the oral bioavailability of sulfonamides have been studied for many decades. Previous studies found that the nitrogen atom of this fragment (as shown in Table V) plays an important role in binding to the receptor and is critical to membrane permeability and bioavailability (45,46). However, the potential mechanisms that are relevant to the bioavailability of sulfonamides are still not well understood.…”

Section: Discussionmentioning

confidence: 99%

Critical Evaluation of Human Oral Bioavailability for Pharmaceutical Drugs by Using Various Cheminformatics Approaches

et al. 2013

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Purpose Oral bioavailability (%F) is a key factor that determines the fate of a new drug in clinical trials. Traditionally, %F is measured using costly and time -consuming experimental tests. Developing computational models to evaluate the %F of new drugs before they are synthesized would be beneficial in the drug discovery process. Methods We employed Combinatorial Quantitative Structure-Activity Relationship approach to develop several computational %F models. We compiled a %F dataset of 995 drugs from public sources. After generating chemical descriptors for each compound, we used random forest, support vector machine, k nearest neighbor, and CASE Ultra to develop the relevant QSAR models. The resulting models were validated using five-fold cross-validation. Results The external predictivity of %F values was poor (R2=0.28, n=995, MAE=24), but was improved (R2=0.40, n=362, MAE=21) by filtering unreliable predictions that had a high probability of interacting with MDR1 and MRP2 transporters. Furthermore, classifying the compounds according to the %F values (%F<50% as “low”, %F≥50% as ‘high”) and developing category QSAR models resulted in an external accuracy of 76%. Conclusions In this study, we developed predictive %F QSAR models that could be used to evaluate new drug compounds, and integrating drug-transporter interactions data greatly benefits the resulting models.

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Section: Discussionmentioning

confidence: 99%

Critical Evaluation of Human Oral Bioavailability for Pharmaceutical Drugs by Using Various Cheminformatics Approaches

et al. 2013

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“…This was discovered by Beecham as the first β 3 -AR agonist, BRL37344 [5,67,68]. In an effort to improve their oral bioavailability, the effect on both their agonistic potency and Caco-2 cell permeability by replacing the sulfonamide portion on the LHS was investigated [70]. Researchers at Dainippon reported a series of arylsulfonamide derivatives such as compound 25 [47,69], which have excellent agonistic profiles in vitro but poor oral bioavailability in rats due to low cell permeability [70].…”

Section: Modification Of Lhsmentioning

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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“…Some N,N-disubstituted tryptamines have been reported to show psychotomimetic activity, although there is evidence to suggest that the tryptamine derivatives are metabolized in vivo to more active forms. In addition, some tryptaminebased sulfonamides have been reported as human b3-adrenergic receptor agonists (Kobeci et al, 2005;Sawa et al, 2005;Yamazaki et al, 2009;Jenkins et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and biological activity studies of new hybrid molecules containing tryptamine moiety

et al. 2010

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The synthesis of N 0 -(4-substitutedphenylsulfonyl)-2-{4-[2-(1H-indol-yl)ethyl]-3-(4-chlorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetohydrazides (3a-c), 2-{4-[2-(1H-indol-3-yl)ethyl]-3-(4-chlorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N 0 -aryl methylidene acetohydrazides (4a-f) and 4-[2-(1H-indol-3-yl)ethyl]-5-(4-substitutedbenzyl)-2-[(5-sulfanyl-1,3,4-oxadiazol-2-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-ones (5a, b) was performed starting from the corresponding acid hydrazides (2a, b) which was reported earlier. The treatment of 1,3,4-oxadiazole derivatives (5a, b) with hydrazine hydrate produced 4-amino-5-sulfanyl-4H-1,2,4-triazol-3-yl derivatives (6a, b). Then, compound 6b was converted to the corresponding Schiff base (7) by the treatment with anisaldehyde. The synthesis of 5-(4-chlorobenzyl)-4-[2-(1H-indol-3-yl)ethyl]-2-[(4-benzyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (8) and 5-(4-methylbenzyl)-4-[2-(1H-indol-3-yl) ethyl]-2-[(4-benzyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (10) was carried out by the reaction of acid hydrazides (2a, b) with aryl iso(thio)cyanates either via the formation of the intermediates (9a, b) (for 10) or direct cyclization (for 8).1,3-Oxa(thia)zol-2(3H)-ylidene]acetohydrazide derivatives (11a, b) were obtained by the reaction of 9a, b with 4-chlorophenacyl bromide. All newly synthesized compounds were screened for their antimicrobial activities and some of which was found to be active against the test microorganisms.

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Tryptamine-based human β3-adrenergic receptor agonists. Part 3: Improved oral bioavailability via modification of the sulfonamide moiety

Cited by 13 publications

References 7 publications

Critical Evaluation of Human Oral Bioavailability for Pharmaceutical Drugs by Using Various Cheminformatics Approaches

Critical Evaluation of Human Oral Bioavailability for Pharmaceutical Drugs by Using Various Cheminformatics Approaches

Subject Index to Volume 12

Synthesis and biological activity studies of new hybrid molecules containing tryptamine moiety

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