Addressing species specific metabolism and solubility issues in a quinoline series of oral PDE4 inhibitors

Lunniss, Christopher J.; Eldred, Colin; Aston, N.M.; Craven, Andrew; Gohil, K.; Judkins, Brian D.; Keeling, Steve; Ranshaw, Lisa E.; Robinson, Eve; Shipley, Tracy J.; Trivedi, Naimisha

doi:10.1016/j.bmcl.2009.11.010

Cited by 31 publications

(13 citation statements)

References 10 publications

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“…87 The compound containing a quinoline (165) had acceptable PK parameters in rat and dog, but they discovered that an oxidized analogue 166 was formed in monkey hepatocytes. This metabolite was synthetically prepared and was found to be more stable than the parent compound in monkey PK studies.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

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Mitigating Heterocycle Metabolism in Drug Discovery

2012

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In the past few decades, drug metabolism research has played an ever increasing role in the design of drugs. 1−3 In vitro metabolism assays 4 have become an integral part of the routine profiling of compounds made in drug discovery. 5 The data from these assays have allowed medicinal chemists to focus their efforts on compounds with improved metabolic stability. 6 Detailed metabolite identification studies are also done more routinely, which provide information on how to strategically replace or block metabolically labile sites. 7 Additionally, in vivo PK studies are regularly conducted in drug discovery, which helps to build in vitro−in vivo PK relationships. 4 The positive influence that these advances in PKDM sciences have had on drug discovery is reflected in the fact that fewer drug candidates fail in the clinic for PKDM related issues. 8 This suggests that medicinal chemists are successfully integrating the data generated by their PKDM colleagues into the design of compounds with fewer metabolic liabilities.Extensive data from metabolism studies have allowed medicinal chemists to develop general principles for reducing compound metabolism. These methods include, but are not limited to, reducing lipophilicity, altering sterics and electronics, introducing a conformational constraint, and altering the stereochemistry of their compounds. While no single method is able to solve every metabolic problem, these principles do give medicinal chemists guidance on how to improve the metabolic liabilities of their compounds. If the specific site of metabolism is known, medicinal chemists block the site, typically with a fluorine, or replace the metabolically labile group with a bioisostere. 9 While several authors have reviewed these techniques for reducing metabolism, 5,10,11 there is no review that summarizes different approaches to improving the metabolic stability of heterocycles. In this review, we summarize examples where changes were made at or near the heterocycle to improve metabolic stability. By summarizing these examples, we hope to provide a useful guide to medicinal chemists as they attempt to improve the metabolic profile of their own heterocyclic compounds.The majority of the examples that are included in this review came from searching the online open access database CHEMBL. 12 In addition to having pharmacology data on compounds from the medicinal chemistry literature, CHEMBL has over 120 000 points of data on the ADMET properties of compounds. With the help of the visualization software Spotfire, we were able to cull examples from the CHEMBL ADMET data that focused on heterocycles. We also identified examples from papers that cite leading reviews in the drug metabolism field 13−18 and were present in other recent reviews on drug metabolism. 19−22 The main criteria that we placed on the examples selected for this review was that the change made to improve metabolism had to occur at or near the heterocycle and nowhere else on the molecule. This allowed us to eliminate examples where a change made t...

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Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

“…In vitro activity and in vivo PK parameters for selected PDE4 inhibitors. 87 The potency data are reported as the inhibition of LPS induced TNF-α production in human whole blood (hWB). higher lipophilicity of 159.…”

Section: ■ Fused Bicyclic Heteroaromaticsmentioning

confidence: 99%

Mitigating Heterocycle Metabolism in Drug Discovery

2012

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“…Cinnolines, and cinnoline derivatives, are known to exhibit anti‐cancer,3 fungicidal and bactericidal,4 and anti‐inflammatory5 activity as well as luminescent and optical properties (Scheme ) 6. Yet these structures remain relatively unfamiliar in modern‐day organic chemistry; when compared with their quinoline isostere, the cinnoline substructure is considerably less exploited.…”

Section: Methodsmentioning

confidence: 99%

Copper‐Catalyzed Tandem CN Bond Formation: An Efficient Annulative Synthesis of Functionalized Cinnolines

Ball¹,

Gilmore²,

Willis³

2012

Angewandte Chemie

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“…Cinnoline moieties are frequently found in biologically active molecules, whereof numerous with attractive pharmacological properties such as antibacterial, anticancer, antimicrobial, anti‐inflammatory, antifungal, antihypertensive, antiulcer, cytotoxic, and topoisomerase inhibitor, see Figure .…”

Section: Figurementioning

confidence: 99%

A Concise Synthesis to Benzo[c ]cinnolines via 2,2’-Dinitro-1,1’-Biphenyls Attained from a Novel Tailored Suzuki Cross-Coupling

Elumalai

Bjørsvik

2017

ChemistrySelect

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A new two‐step synthetic process for the preparation of unsymmetrically substituted benzo[c]cinnolines was developed. The key intermediate 2,2’‐dinitro‐1,1’‐biphenyl was prepared by means of an unprecedented tailored Suzuki cross‐coupling protocol. The subsequent step is constituted by a domino partial nitro group reduction and intramolecular diazo bond formation, a process that afford target benzo[c]cinnoline scaffold. The disclosed method tolerates both electron‐withdrawing‐ and electron‐donating groups.

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Addressing species specific metabolism and solubility issues in a quinoline series of oral PDE4 inhibitors

Cited by 31 publications

References 10 publications

Mitigating Heterocycle Metabolism in Drug Discovery

Mitigating Heterocycle Metabolism in Drug Discovery

Copper‐Catalyzed Tandem CN Bond Formation: An Efficient Annulative Synthesis of Functionalized Cinnolines

A Concise Synthesis to Benzo[c ]cinnolines via 2,2’-Dinitro-1,1’-Biphenyls Attained from a Novel Tailored Suzuki Cross-Coupling

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