2-(2-Aminothiazol-4-yl)pyrrolidine-based tartrate diamides as potent, selective and orally bioavailable TACE inhibitors

Dai, Chaoyang; Li, Dansu; Popovici‐Muller, Janeta; Zhao, Long; Girijavallabhan, Vinay; Rösner, K; Lavey, Brian J.; Rizvi, Razia; Shankar, B. B.; Wong, Michael; Guo, Zhuyan; Orth, Peter; Strickland, Corey; Sun, Jing; Niu, Xiaoda; Chen, Shiying; Kozlowski, Joseph A.; Lundell, Daniel; Piwinski, John J.; Shih, Neng‐Yang; Siddiqui, M. Arshad

doi:10.1016/j.bmcl.2011.01.002

Cited by 26 publications

(33 citation statements)

References 25 publications

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“…582 One such derivative is ADAMi-10, which maintains selectivity over ADAM-10, has an inhibition constant of 5 nM, and has improved oral bioavailability compared to earlier tartrate inhibitors. 582…”

Section: Peptidases (Ec 34)mentioning

confidence: 99%

Targeting Metalloenzymes for Therapeutic Intervention

et al. 2018

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Metalloenzymes are central to a wide range of essential biological activities, including nucleic acid modification, protein degradation, and many others. The role of metalloenzymes in these processes also makes them central for the progression of many diseases and, as such, makes metalloenzymes attractive targets for therapeutic intervention. Increasing awareness of the role metalloenzymes play in disease and their importance as a class of targets has amplified interest in the development of new strategies to develop inhibitors and ultimately useful drugs. In this Review, we provide a broad overview of several drug discovery efforts focused on metalloenzymes and attempt to map out the current landscape of high-value metalloenzyme targets.

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Section: Peptidases (Ec 34)mentioning

confidence: 99%

Targeting Metalloenzymes for Therapeutic Intervention

et al. 2018

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“…As seen in Fig. 5A–B, no overlap of the MEDI3622 epitope and the footprints of small molecule-based inhibitors and TIMP-3 is observed when the MEDI3622/M-domain model complex is superimposed with the M-domains bound with small molecule inhibitors (PDB 3LE9 19 and 3O64 20 ) or the N-terminal domain of TIMP-3 (PDB 3CKI 18 ). Furthermore, we confirmed that MEDI3622 and TIMP-3 bound concurrently to TACE (Fig.…”

Section: Resultsmentioning

confidence: 95%

“…(A) The binding mode of MEDI3622 appears different from TACE small molecule and natural protein inhibitors upon structure alignments. (Left) The model of the MEDI3622 (V H orange and V L beige)/TACE (magenta) complex was superimposed to crystal structures of TACE M-domains complexed with small molecule inhibitors (PDB 3LE9 19 and 3O64 20 ) through the common TACE M-domains. The M-domains for 3LE9 and 3O64 were shown in light pink and pale green and their bound small molecule inhibitors were displayed in yellow and blue sticks, respectively.…”

Section: Resultsmentioning

confidence: 99%

Molecular basis for the mechanism of action of an anti-TACE antibody

Li¹,

Cook²,

Xu³

et al. 2016

mAbs

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Inhibitors of tumor necrosis factor-α converting enzyme (TACE) have potential as therapeutics for various diseases. Many small molecule inhibitors, however, exhibit poor specificity profiles because they target the highly conserved catalytic cleft of TACE. We report for the first time the molecular interaction of a highly specific anti-TACE antagonistic antibody (MEDI3622). We characterized the binding of MEDI3622 using mutagenesis, as well as structural modeling and docking approaches. We show that MEDI3622 recognizes a unique surface loop of sIVa-sIVb β-hairpin on TACE M-domain, but does not interact with the conserved catalytic cleft or its nearby regions. The exquisite specificity of MEDI3622 is mediated by this distinct structural feature on the TACE M-domain. These findings may aid the design of antibody therapies against TACE.

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“…In 2011, Dai et al at Merck turned their attention to optimizing the LHS amine building blocks in the hope of improving their oral PK profiles while maintaining or further improving its biochemical potencies [138]. The high binding affinities were largely maintained in compounds with mono-alkyl N-substitutions, the cyclopropyl compound 97-1 ( Table 4) showed remarkably high AUCs (134267 nM.…”

Section: Tartrate-based Tace Inhibitorsmentioning

confidence: 99%

Discovery of Selective Small Molecular TACE Inhibitors for the Treatment of Rheumatoid Arthritis

Shi²,

Tang³

et al. 2012

CMC

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Rheumatoid arthritis (RA) is a chronic, inflammatory disease that afflicts 1-2% of the world population, characterized by an immune mediated inflammatory synovitis that leads to joint destruction, functional impairment, and reduced quality of life. The treatment goals of RA should be longterm substantial relief of pain, arrested joint inflammation and damage, and improved function. Current treatment can be divided into four classes, namely general analgesics and non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, disease modifying anti-rheumatic drugs (DMARDs) and biological agents (tumor-necrosis factor modifiers). However, gastrointestinal (GI) side effects of NSAIDs cannot be neglected, direct joint injections of glucocorticoids cannot be injected more than once every 3 months, synthetic DMARDs is far from optimal and only minority of patients achieved longterm remission, the biologics are very expensive to manufacture, need to be injected, and can cause allergic reactions. An alternative and good approach to the treatment of this disease is to lower the levels of tumour necrosis factor-α (TNF-α) in RA, which can be achieved by selectively inhibiting the tumour necrosis factor-α converting enzyme (TACE) that generate these cytokines using cheaper small molecules. This review focuses on the current status of selective small molecule inhibitors of TACE, with respect to lead compound search, inhibitors design approach, structure-activity relationship (SAR) and pharmacological studies in animals and humans. Through these methods, new hope is emerging for the treatment of RA through selective inhibition of TACE.

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2-(2-Aminothiazol-4-yl)pyrrolidine-based tartrate diamides as potent, selective and orally bioavailable TACE inhibitors

Cited by 26 publications

References 25 publications

Targeting Metalloenzymes for Therapeutic Intervention

Targeting Metalloenzymes for Therapeutic Intervention

Molecular basis for the mechanism of action of an anti-TACE antibody

Discovery of Selective Small Molecular TACE Inhibitors for the Treatment of Rheumatoid Arthritis

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