Synthesis and SAR of 2-phenyl-1-sulfonylaminocyclopropane carboxylates as ADAMTS-5 (Aggrecanase-2) inhibitors

Shiozaki, Makoto; Imai, Hiroto; Maeda, Kazuyuki; Miura, Tomoya; Yasue, Katsutaka; Suma, Akira; Yokota, Masahiro; Ogoshi, Yosuke; Haas, Julia; Fryer, Andrew M.; Laird, Ellen R.; Littmann, Nicole M.; Andrews, Steven W.; Josey, John A.; Mimura, Takayuki; Shinozaki, Yuichi; Yoshiuchi, Hiromi; Inaba, Takashi

doi:10.1016/j.bmcl.2009.08.093

Cited by 19 publications

(13 citation statements)

References 20 publications

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“…Yet another series of compounds, α-glutamic acid scaffold based 4-(benzamido)-4-(1,3,4-oxadiazol-2-yl) butanoic acids, have been designed and synthesized to inhibit the activity of both ADAMTS4 and ADAMTS5 [ 89 ]. Furthermore, a series of 1-sulfonylaminocyclopropanecarboxylates and N-substituted sulfonylamino-alkanecarboxylates are potent ADAMTS5 inhibitors with good selectivity over MMPs such as MMP-1 [ 90 ]. More recently, potent and selective novel ADAMTS5 inhibitor scaffolds which lacked a zinc-binding motif and which contained a 1,3,5-triazine core were designed [ 91 ].…”

Section: The Development Of Small-molecule Inhibitors Of the Aggrecanmentioning

confidence: 99%

Current and emerging therapeutic strategies for preventing inflammation and aggrecanase-mediated cartilage destruction in arthritis

Dancevic

McCulloch

2014

Arthritis Res Ther

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Arthritis is a multifactorial disease for which current therapeutic intervention with high efficacy remains challenging. Arthritis predominately affects articular joints, and cartilage deterioration and inflammation are key characteristics. Current therapeutics targeting inflammatory responses often cause severe side effects in patients because of the systemic inhibition of cytokines or other global immunosuppressive activities. Furthermore, a lack of primary response or failure to sustain a response to treatment through acquired drug resistance is an ongoing concern. Nevertheless, treatments such as disease-modifying anti-rheumatic drugs, biological agents, and corticosteroids have revealed promising outcomes by decreasing pain and inflammation in patients and in some cases reducing radiographic progression of the disease. Emerging and anecdotal therapeutics with anti-inflammatory activity, alongside specific inhibitors of the A Disintegrin-like And Metalloproteinase domain with Thrombospondin-1 repeats (ADAMTS) cartilage-degrading aggrecanases, provide promising additions to current arthritis treatment strategies. Thus, it is paramount that treatment strategies be optimized to increase efficacy, reduce debilitating side effects, and improve the quality of life of patients with arthritis. Here, we review the current strategies that attempt to slow or halt the progression of osteoarthritis and rheumatoid arthritis, providing an up-to-date summary of pharmaceutical treatment strategies and side effects. Importantly, we highlight their potential to indirectly regulate ADAMTS aggrecanase activity through their targeting of inflammatory mediators, thus providing insight into a mechanism by which they might inhibit cartilage destruction to slow or halt radiographic progression of the disease. We also contrast these with anecdotal or experimental administration of statins that could equally regulate ADAMTS aggrecanase activity and are available to arthritis sufferers worldwide. Finally, we review the current literature regarding the development of synthetic inhibitors directed toward the aggrecanases ADAMTS4 and ADAMTS5, a strategy that might directly inhibit cartilage destruction and restore joint function in both rheumatoid arthritis and osteoarthritis.

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Section: The Development Of Small-molecule Inhibitors Of the Aggrecanmentioning

confidence: 99%

Current and emerging therapeutic strategies for preventing inflammation and aggrecanase-mediated cartilage destruction in arthritis

Dancevic

McCulloch

2014

Arthritis Res Ther

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“…A series of peptidic nitriles was shown to inhibit cathepsin C, the nitrile taking the place of a carboxy group in the corresponding dipeptide; the most effective substituents alpha to the nitrile was a cyclopropane ring, as in the lead compound 5 (Fig. 2) which was stable to hydrolysis in rat whole blood after 30 min, >98% of the nitrile remaining (IC 50 of 5 against cathepsin C=14 nM, using human recombinant enzyme); this efficacy is in striking contrast to the cyclobutane analogue that showed only micromolar activity against cathepsin C. 5 A series of 1-sulfonamidocyclopropanecarboxylates was investigated for potential to combat osteoarthritis, 6 which involves degradation of aggrecan, the major proteoglycan in cartilage. Compound 6, (Fig.…”

Section: Cycloalkanes and Spirocarbocyclic And Fused Carbocyclic Syst...mentioning

confidence: 99%

New and unusual scaffolds in medicinal chemistry

2011

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Contemporary medicinal chemistry faces diverse challenges from several directions, including the need for both potency and specificity of any therapeutic agent; the increasingly demanding requirements of low toxicity shown across all patients treated; and the need for novelty in intellectual property, given the extensive use of benzenoid and heteroaromatic ring systems in numerous patents. Increasingly, such challenges are being met by a shift to new and/or unusual ring systems (scaffolds) that lie outside the field of (hetero)aromatic systems. This critical review surveys a necessarily limited selection of currently atypical scaffolds, chiefly drawn from the literature of the last three years, that have found application in medicinal chemistry, some being present in agents with therapeutic potential while others are found in agents already in clinical use (163 references).

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“…Most of the reported methods required multistep manipulation or environmentally unfriendly reagents . Particularly, compared with the single quaternary carbon stereocenter, adjacent quaternary-tetrasubstituted carbon centers can enhance the conformational constraints and show more advantages in pharmacokinetic profiles, even making further improvement on the biological activity . Therefore, the development of one-step and eco-friendly methods for the synthesis of aminocyclopropanephosphonates with adjacent quaternary-tetrasubstituted carbon centers is a challenging issue.…”

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confidence: 99%

Transition-Metal-Free [3+2] Cycloaddition of Dehydroaminophosphonates and N-Tosylhydrazones: Access to Aminocyclopropanephosphonates with Adjacent Quaternary-Tetrasubstituted Carbon Centers

Lin

Zhu

et al. 2017

J. Org. Chem.

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A novel one-step strategy for the synthesis of aminocyclopropanephosphonates containing adjacent quaternary-tetrasubstituted carbon centers under transition-metal-free catalysis via [3+2] cycloaddition process has been developed. A series of aminocyclopropanephosphonates with adjacent quaternary-tetrasubstituted carbon centers including spirocyclopropyl adducts were obtained in moderate to excellent yields under mild reaction conditions. This protocol would find the potential applications in biochemistry and medicinal chemistry.

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Synthesis and SAR of 2-phenyl-1-sulfonylaminocyclopropane carboxylates as ADAMTS-5 (Aggrecanase-2) inhibitors

Cited by 19 publications

References 20 publications

Current and emerging therapeutic strategies for preventing inflammation and aggrecanase-mediated cartilage destruction in arthritis

Current and emerging therapeutic strategies for preventing inflammation and aggrecanase-mediated cartilage destruction in arthritis

New and unusual scaffolds in medicinal chemistry

Transition-Metal-Free [3+2] Cycloaddition of Dehydroaminophosphonates and N-Tosylhydrazones: Access to Aminocyclopropanephosphonates with Adjacent Quaternary-Tetrasubstituted Carbon Centers

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