Potent Cholesteryl Ester Transfer Protein Inhibitors of Reduced Lipophilicity: 1,1′-Spiro-Substituted Hexahydrofuroquinoline Derivatives

Trieselmann, Thomas; Wagner, H.; Fuchs, Klaus; Hamprecht, Dieter; Berta, Daniela; Cremonesi, Paolo; Streicher, Rüdiger; Luippold, Gerd; Volz, Astrid; Markert, Michael; Nar, Herbert

doi:10.1021/jm500431d

Cited by 24 publications

(16 citation statements)

References 34 publications

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“…233 Moreover, the high lipophilicity of these molecules contributes to their very long elimination halflives in humans, with terminal t 1/2 values ranging from 44 to 221 h. However, molecules in this quadrant of the MW/cLog P graph are not essential for potent CETP inhibitors, as demonstrated by the optimization of 36 into 38. 234 The originating molecule 36 is related to BAY 38-1315 (39), a compound with a cLog P of 8.6 (calculated using ChemBioDraw v14.0) that was halted in preclinical development due to poor PK properties. 235 While 36 had a lower MW but similar LLE (LipE), LE, and LLE AT values to those of the prototypical CETP inhibitors, it was hypothesized that conformational restriction of the fluorobenzyl side chain moiety would lead to enhanced potency.…”

Section: + + #mentioning

confidence: 99%

“…235 While 36 had a lower MW but similar LLE (LipE), LE, and LLE AT values to those of the prototypical CETP inhibitors, it was hypothesized that conformational restriction of the fluorobenzyl side chain moiety would lead to enhanced potency. 234 After some experimentation, the cyclic compound 37 was identified as a constrained analogue that retained potency while reducing lipophilicity, leading to a now positive value for LLE (LipE) and an increase in both LLE AT and LE that was accompanied by a reduction in LELP. Additional modifications sought to further refine potency while controlling lipophilicity, leading to the spiro tetrahydropyran derivative 38 as a compound that offered an optimal compromise within the series.…”

Section: + + #mentioning

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.

180

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: + + #mentioning

confidence: 99%

Section: + + #mentioning

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.

180

133

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“…Furoquinoline scaffolds are one of the important heterocycles and their analogues are found not only in nature but also in pharmacological and biological materials, whose properties include anti‐inflammatory, TLR8 (Toll‐like receptor‐8) agonistic, anti‐cancerous, a protein inhibitory, and antimicrobial activity . Owing to their diverse biological activities, there have been great efforts to extract or synthesize furoquinolines, i.e ., [3 + 2] cyclization reaction for furo[2,3‐ b ]quinolines, [4 + 2] cycloaddition of imines with enol ethers, and a three component reaction of 4‐hydroxyquinolin‐2( 1H )‐one, aromatic aldehyde and isonitrile, and so on .…”

Section: Methodsmentioning

confidence: 99%

Synthesis of 2‐Substituted Furo[2,3‐b]‐ and Furo[3,2‐c]quinolines via Heterogeneous Palladium‐catalyzed Heteroannulation

Park

Yang

Park

et al. 2016

Bulletin Korean Chem Soc

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Furoquinoline scaffolds are one of the important heterocycles and their analogues are found not only in nature 1 but also in pharmacological and biological materials, whose properties include anti-inflammatory, 2 TLR8 (Toll-like receptor-8) agonistic, 3 anti-cancerous, 4 a protein inhibitory, 5 and antimicrobial activity. 6 Owing to their diverse biological activities, there have been great efforts to extract 7 or synthesize furoquinolines, i.e., [3 + 2] cyclization reaction for furo [2,3-b]quinolines, 8 [4 + 2] cycloaddition of imines with enol ethers, 9 and a three component reaction of 4-hydroxyquinolin-2(1H)-one, aromatic aldehyde and isonitrile, and so on. 10 Recently we have paid much attentions to develop green and practical synthetic methods for synthesizing various furoheterocycles 1-6 as shown in Scheme 1. 11 The isomeric 2-substituted furopyridines such as furo[3,2b]-, furo[2,3-b]-, and furo[3,2-c]pyridine were synthesized starting from o-halohydroxypyridines and terminal alkynes catalyzed by commercial Pd/C under copper-and ligandfree conditions. Also we were able to show diversification of our protocol to make 2,3-disubstituted furoquinolines, 5 and 6, by Suzuki and Heck reactions, respectively. 11a As a part of our continuing organometallic studies on diversification of nitrogen-containing biologically active heterocycles, we attempted to synthesize furo[2,3-b]-and furo[3,2-c]quinolines starting from o-halohydroxyquinolines and terminal alkynes with heterogeneous Pd(OAc) 2 catalyst, which was supported by nanosized pore carbon ball. The best reaction condition was obtained under CNB-Pd(OAc) 2

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“…Within 21 days 32 eliminates completely from fat tissue in hCETP transgenic mice. Furthermore, robust elevation of HDL‐C levels and reduction of LDL‐C levels could be demonstrated in hCETP/hApoB‐100 mice …”

Section: Acyltransferasesmentioning

confidence: 96%

“…Furthermore, robust elevation of HDL-Cl evels and reduction of LDL-C levels could be demonstrated in hCETP/hApoB-100 mice. [132]…”

Section: Extracellular Lipid Transferasesmentioning

confidence: 99%

Chemical Genetic Approaches for the Investigation of Neutral Lipid Metabolism

et al. 2016

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The coordinated processes of lipid synthesis, degradation, and transport are mediated by enzymes, cofactors, and transport proteins. Accordingly, lipid-metabolizing enzymes represent logical targets for the treatment of dyslipidemia, a major risk factor for type 2 diabetes, atherosclerosis, and other disorders. Small-molecule tool compounds, modulating the functions of such proteins, can substantially facilitate the characterization of target proteins. Such molecules complement genetic studies, and allow time- and dose-dependent control of protein activity in biological systems. This can improve our understanding of physiological processes, give insights into the druggability of target proteins, and might finally result in the development of therapeutic compounds. In this review we summarize the current state of available inhibitors targeting key proteins in neutral lipid metabolism, with a focus on metabolic lipases, acyltransferases, and fatty-acid-binding proteins.

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Potent Cholesteryl Ester Transfer Protein Inhibitors of Reduced Lipophilicity: 1,1′-Spiro-Substituted Hexahydrofuroquinoline Derivatives

Cited by 24 publications

References 34 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

Synthesis of 2‐Substituted Furo[2,3‐b]‐ and Furo[3,2‐c]quinolines via Heterogeneous Palladium‐catalyzed Heteroannulation

Chemical Genetic Approaches for the Investigation of Neutral Lipid Metabolism

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