Discovery of novel pyrimidine and malonamide derivatives as TGR5 agonists

Park, Eun Ju; Ahn, Young Gil; Jung, Seung Hyun; Bang, Hyo Jeong; Kim, Mi-Ra; Hong, Dong Jin; Kim, Jisook; Suh, Kwee Hyun; Kim, Young Jin; Kim, Doran; Kim, Eun-Yeong; Lee, Kiho; Min, Kyung Hoon

doi:10.1016/j.bmcl.2014.07.026

Cited by 12 publications

(10 citation statements)

References 14 publications

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“…The intrinsic potency of the two compounds is comparable, but in this example, modification of the pyridine ring led to a significant decrease of 2.5 units in cLog P and cLog D pH7 values which resulted in improvements in the LLE (LipE), LLE AT , and LELP values, while the Fsp 3 count doubled, and the value of cLog D pH7 + #Ar was halved. 275 Unfortunately, the effect of these changes in compound quality on developability parameters was not explored in any detail.…”

Section: Bicyclo[111]pentane As a Phenylmentioning

confidence: 99%

“…This approach to the replacement of the problematic 1,2-diaminopyridine structural element was shown to extend to both a series of factor Xa inhibitors and agonists of the bile acid receptor GPBAR1 (TGR5). − The comparative biological activity, physicochemical data, and calculated efficiency indices for the two TGR5 agonists 116 and 117 are compiled in Table . The intrinsic potency of the two compounds is comparable, but in this example, modification of the pyridine ring led to a significant decrease of 2.5 units in cLog P and cLog D pH7 values which resulted in improvements in the LLE (LipE), LLE AT , and LELP values, while the Fsp 3 count doubled, and the value of cLog D pH7 + #Ar was halved . Unfortunately, the effect of these changes in compound quality on developability parameters was not explored in any detail.…”

Section: Approaches To Increasing Fsp3 In Drug Designmentioning

confidence: 99%

See 1 more Smart Citation

Improving Drug Design: An Update on Recent Applications of Efficiency Metrics, Strategies for Replacing Problematic Elements, and Compounds in Nontraditional Drug Space

Meanwell

2016

Chem. Res. Toxicol.

170

133

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Drug discovery and development is a complex and lengthy enterprise that suffers from high rates of candidate attrition at all stages of the process. The physical, biological, and toxicological properties of a drug candidate are inextricably linked to its structure, and once a molecule has been synthesized, all subsequent studies along the development path are focused only on assessing and understanding its properties in greater detail. Unfortunately, a full prediction of the biological properties of a molecule from an analysis of its 2- or 3-dimensional structure is currently beyond our expertise. This backdrop mandates that considerable care be taken at the design stage if a molecule is to be successful in testing a mechanistic concept underlying a disease process and to progress into late stage clinical trials and, ultimately, marketing approval. While there are multiple potential causes of candidate attrition, an introspective analysis of drug design practices over the past decade has focused attention on the perception that contemporary molecules are unnecessarily obese, burdened by high molecular weight and excessive lipophilicity. This practice is believed to have its roots in the singular pursuit of enhancing potency during lead optimization rather than adopting a more holistic approach to drug design that gives broader consideration to how structural features affect developability properties. In an effort to provide the medicinal chemistry community with practical guideposts to enhancing compound quality in the drug design phase and which can readily be applied, a series of efficiency indices have been proposed that attempt to define aspects of compound quality in the context of a series of physicochemical parameters. Of these metrics, lipophilic ligand efficiency (LLE or LipE), which provides an index of the dependence of the potency of a molecule on its intrinsic lipophilicity, has been characterized as the most robust metric that has potential for broad-based application. In this review, after describing the background literature behind the derivation of efficiency metrics and approaches to assessing compound aesthetics, synopses of some recent practical application in lead optimization campaigns are presented. However, molecules that fall into space beyond that associated with traditional drug-like properties are an important part of the current and future landscape, exemplified by the summary of direct acting hepatitis C virus NS3 and NS5A inhibitors that have transformed clinical therapy for this chronic disease. While drug development in nontraditional drug-like space is more challenging and the rules for compound quality will be different with much still to be understood, careful and disciplined drug design practices will be an essential element of success.

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Section: Bicyclo[111]pentane As a Phenylmentioning

confidence: 99%

Section: Approaches To Increasing Fsp3 In Drug Designmentioning

confidence: 99%

Improving Drug Design: An Update on Recent Applications of Efficiency Metrics, Strategies for Replacing Problematic Elements, and Compounds in Nontraditional Drug Space

Meanwell

2016

Chem. Res. Toxicol.

170

133

View full text Add to dashboard Cite

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“…Beside bioassay-guided fractionation of plant extracts (Sato et al, 2007 ), bioisosteric replacement (Park et al, 2014 ), and exploitation/lead optimization of bile acid scaffolds (Pellicciari et al, 2009 ), previous efforts in the discovery of GPBAR1 modulators have focused on high throughput screening (HTS) (Evans et al, 2009 ; Herbert et al, 2010 ; Londregan et al, 2013 ; Martin et al, 2013 ) leading to a broad range of agonists of which some are depicted in Figure 1 .…”

Section: Introductionmentioning

confidence: 99%

In Silico Workflow for the Discovery of Natural Products Activating the G Protein-Coupled Bile Acid Receptor 1

et al. 2018

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The G protein-coupled bile acid receptor (GPBAR1) has been recognized as a promising new target for the treatment of diverse diseases, including obesity, type 2 diabetes, fatty liver disease and atherosclerosis. The identification of novel and potent GPBAR1 agonists is highly relevant, as these diseases are on the rise and pharmacological unmet therapeutic needs are pervasive. Therefore, the aim of this study was to develop a proficient workflow for the in silico prediction of GPBAR1 activating compounds, primarily from natural sources. A protocol was set up, starting with a comprehensive collection of structural information of known ligands. This information was used to generate ligand-based pharmacophore models in LigandScout 4.08 Advanced. After theoretical validation, the two most promising models, namely BAMS22 and TTM8, were employed as queries for the virtual screening of natural product and synthetic small molecule databases. Virtual hits were progressed to shape matching experiments and physicochemical clustering. Out of 33 diverse virtual hits subjected to experimental testing using a reporter gene-based assay, two natural products, farnesiferol B (27) and microlobidene (28), were confirmed as GPBAR1 activators reaching more than 50% receptor activation at 20 μM with EC50s of 13.53 μM and 13.88 μM, respectively. This activity is comparable to that of the endogenous ligand lithocholic acid (1). Seven further virtual hits showed activity reaching at least 15% receptor activation either at 5 or 20 μM, including new scaffolds from natural and synthetic origin.

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“…More recently, this motif has been explored in the context of a Takeda G-protein-coupled receptor 5 (TGR5) agonist where the pyridine backbone of 86c was successfully replaced with a cyclopropyl carbonyl moiety. This molecular edit fully preserved potency in a cell-based assay that assessed cAMP levels in response to the application of 86d (Figure B) . Unfortunately, detailed developability profiling data associated with 86d were not disclosed; hence, the full potential and advantages of this bioisostere in this specific context remains enigmatic.…”

Section: Bioisosteric Replacement Of Ortho-substituted Phenyl Ringsmentioning

confidence: 99%

Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design

2021

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The benzene moiety is the most prevalent ring system in marketed drugs, underscoring its historic popularity in drug design either as a pharmacophore or as a scaffold that projects pharmacophoric elements. However, introspective analyses of medicinal chemistry practices at the beginning of the 21st century highlighted the indiscriminate deployment of phenyl rings as an important contributor to the poor physicochemical properties of advanced molecules, which limited their prospects of being developed into effective drugs. This Perspective deliberates on the design and applications of bioisosteric replacements for a phenyl ring that have provided practical solutions to a range of developability problems frequently encountered in lead optimization campaigns. While the effect of phenyl ring replacements on compound properties is contextual in nature, bioisosteric substitution can lead to enhanced potency, solubility, and metabolic stability while reducing lipophilicity, plasma protein binding, phospholipidosis potential, and inhibition of cytochrome P450 enzymes and the hERG channel.

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Discovery of novel pyrimidine and malonamide derivatives as TGR5 agonists

Cited by 12 publications

References 14 publications

Improving Drug Design: An Update on Recent Applications of Efficiency Metrics, Strategies for Replacing Problematic Elements, and Compounds in Nontraditional Drug Space

Improving Drug Design: An Update on Recent Applications of Efficiency Metrics, Strategies for Replacing Problematic Elements, and Compounds in Nontraditional Drug Space

In Silico Workflow for the Discovery of Natural Products Activating the G Protein-Coupled Bile Acid Receptor 1

Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design

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