SAR studies of non-zinc-chelating MMP-13 inhibitors: Improving selectivity and metabolic stability

Gao, Donghong A.; Xiong, Zhaoming; Heim-Riether, Alexander; Amodeo, Laura; August, Elias; Cao, Xianhua; Ciccarelli, Leonard; Collins, Brandon; Harrington, Kyle E.; Haverty, Kathleen; Hill-Drzewi, Melissa; Li, Xiang; Liang, Shuang; Margarit, S.M.; Moss, Neil; Nagaraja, N.; Proudfoot, John; Roman, Rene; Schlyer, Sabine; Keenan, Lana Smith; Taylor, Steven J.; Wellenzohn, Bernd; Wiedenmayer, Dieter; Li, Jun; Farrow, Neil A.

doi:10.1016/j.bmcl.2010.07.036

Cited by 29 publications

(25 citation statements)

References 34 publications

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“…72 The pyrimidine analogue 125 was marginally more metabolically stable than the corresponding pyridine analogue 123. However, for the analogues where R 1 = C(OH)Me 2 , the metabolic stability of the pyrimidine analogue 126 was significantly better than the pyridine analogue 124.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

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%

Mitigating Heterocycle Metabolism in Drug Discovery

2012

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“…Compound 40 (Figure ) penetrated the S1′ pocket more deeply, which resulted in an inhibitor combining an IC 50 value of 4 n m with >100‐fold selectivity against MMP‐2, ‐8, ‐9, and ‐12 and lower selectivity against MMP‐3 and ‐10, with factors of 45‐ and 24‐fold, respectively . Structural modifications led to 41 (Figure ) with improved selectivity and conserved potency (IC 50 =5 n m ) . Selectivity was enhanced through modification of the interactions formed within the S1′ pocket.…”

Section: Mmp Inhibitorsmentioning

confidence: 99%

Design and Structural Evolution of Matrix Metalloproteinase Inhibitors

Fischer

Senn

Riedl

2019

Chemistry A European J

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Matrix metalloproteinases (MMPs) are involved in a multitude of severe diseases. Despite MMPs being considered druggable targets, past drug‐discovery programs have not delivered the anticipated clinical benefits. This review examines the latest structural evolution of small‐molecule inhibitors of MMPs, with a focus on the development of novel chemical entities with improved affinity and selectivity profiles. X‐ray crystallographic data of the protein targets and cocrystal structures with inhibitors proved to be key for the success achieved during this ambitious endeavor. An evolutionary view on the structural diversity generated for this class of molecules is provided. This encouraging development paves the way for the clinical utilization of this class of highly relevant therapeutic targets. The structure‐based design of superior MMP inhibitors highlights the power of this technique and displays strategies for the development of treatment options based on the modulation of challenging drug targets.

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“…7 Non zinc-chelating inhibitors have been reported for MMP-8, 85 MMP-12 [86][87][88] and MMP-13 [89][90][91][92][93][94][95][96][97][98][99] . The enthusiasm for non zinc-chelating inhibitors started with the discovery of compound 29 at Sanofi laboratories.…”

Section: Positive Impactmentioning

confidence: 99%

Targeting Matrix Metalloproteinases: Exploring the Dynamics of the S1′ Pocket in the Design of Selective, Small Molecule Inhibitors

2014

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Matrix metalloproteinases (MMPs) are important targets for pathological conditions such as arthritis, chronic obstructive pulmonary disease, and cancer. The failure of the first broad-spectrum MMP inhibitors in clinical trials has led researchers to address the selectivity as one of their main objectives. The S1' pocket has been widely used to modulate the selectivity of these enzymes because it displays the highest variability in length and shape among MMPs. In this review, we encourage medicinal chemists to also consider the dynamics of this pocket as an important parameter to achieve the desired selectivity. To support this proposal, we collect examples from the literature where the flexibility of the S1' pocket was highlighted as a relevant and significant issue affecting selectivity. We also review the experimental studies on the dynamics of this pocket.

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SAR studies of non-zinc-chelating MMP-13 inhibitors: Improving selectivity and metabolic stability

Cited by 29 publications

References 34 publications

Mitigating Heterocycle Metabolism in Drug Discovery

Mitigating Heterocycle Metabolism in Drug Discovery

Design and Structural Evolution of Matrix Metalloproteinase Inhibitors

Targeting Matrix Metalloproteinases: Exploring the Dynamics of the S1′ Pocket in the Design of Selective, Small Molecule Inhibitors

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