A Highly Selective Hydantoin Inhibitor of Aggrecanase-1 and Aggrecanase-2 with a Low Projected Human Dose

Durham, Timothy B.; Marimuthu, Jothirajah; Toth, John E.; Liu, Chin; Adams, Luke A.; Mudra, Daniel R.; Swearingen, Craig; Lin, Chaohua; Chambers, M.G.; Thirunavukkarasu, Kannan; Wiley, Michael R.

doi:10.1021/acs.jmedchem.7b00650

Cited by 13 publications

(19 citation statements)

References 26 publications

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“…While NH hydantoins had been reported as ZBGs, , they have been less explored than carboxylic and hydroxamic acids as metalloproteinases inhibitors. Interestingly, during the course of our investigations, Eli Lilly also reported a hydantoin ADAMTS-5 inhibitor. , …”

Section: Resultsmentioning

confidence: 68%

“…To our knowledge, despite several drug development programs, only one ADAMTS-5 small molecule inhibitor has entered clinical development for the treatment of OA, AGG-523, a dual ADAMTS-5/4 inhibitor developed by Wyeth/Pfizer (Table ). − Several pharmaceutical companies have opted to develop monoclonal antibodies that neutralize ADAMTS-5, demonstrating the challenge to develop small molecules targeting this enzyme.…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, during the course of our investigations, Eli Lilly also reported a hydantoin ADAMTS-5 inhibitor. 16,20 Our series displayed a similar potency against rn-and hs-ADAMTS-5 (Figure S1). The properties of compound 1, selected as the hit compound from the hydantoin series, are summarized in Table 2.…”

Section: ■ Introductionmentioning

confidence: 99%

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Discovery of GLPG1972/S201086, a Potent, Selective, and Orally Bioavailable ADAMTS-5 Inhibitor for the Treatment of Osteoarthritis

et al. 2021

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There are currently no approved disease-modifying osteoarthritis (OA) drugs (DMOADs). The aggrecanase ADAMTS-5 is key in the degradation of human aggrecan (AGC), a component of cartilage. Therefore, ADAMTS-5 is a promising target for the identification of DMOADs. We describe the discovery of GLPG1972/S201086, a potent and selective ADAMTS-5 inhibitor obtained by optimization of a promising hydantoin series following an HTS. Biochemical activity against rat and human ADAMTS-5 was assessed via a fluorescence-based assay. ADAMTS-5 inhibitory activity was confirmed with human aggrecan using an AGC ELISA. The most promising compounds were selected based on reduction of glycosaminoglycan release after interleukin-1 stimulation in mouse cartilage explants and led to the discovery of GLPG1972/S201086. The anticatabolic activity was confirmed in mouse cartilage explants (IC50 < 1.5 μM). The cocrystal structure of GLPG1972/S201086 with human recombinant ADAMTS-5 is discussed. GLPG1972/S201086 has been investigated in a phase 2 clinical study in patients with knee OA (NCT03595618).

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Section: Resultsmentioning

confidence: 68%

Section: Introductionmentioning

confidence: 99%

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Discovery of GLPG1972/S201086, a Potent, Selective, and Orally Bioavailable ADAMTS-5 Inhibitor for the Treatment of Osteoarthritis

et al. 2021

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“…Strategically designed additional experiments are needed to dissect out contributions from cochlin deficiency in the inner ear and cochlin deficiency in the middle ear as the latter causes conductive hearing loss and effectively reduces noise input to the inner ear. These future experiments could involve mouse models lacking cochlin in the inner ear only or middle ear only, as well as pharmacologic ( Durham et al, 2017 ) or genetic inhibition of aggrecanases.…”

Section: Discussionmentioning

confidence: 99%

Cochlin Deficiency Protects Against Noise-Induced Hearing Loss

Seist

Landegger

Robertson

et al. 2021

Front. Mol. Neurosci.

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Cochlin is the most abundant protein in the inner ear. To study its function in response to noise trauma, we exposed adolescent wild-type (Coch+/+) and cochlin knock-out (Coch–/–) mice to noise (8–16 kHz, 103 dB SPL, 2 h) that causes a permanent threshold shift and hair cell loss. Two weeks after noise exposure, Coch–/– mice had substantially less elevation in noise-induced auditory thresholds and hair cell loss than Coch+/+ mice, consistent with cochlin deficiency providing protection from noise trauma. Comparison of pre-noise exposure thresholds of auditory brain stem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) in Coch–/– mice and Coch+/+ littermates revealed a small and significant elevation in thresholds of Coch–/– mice, overall consistent with a small conductive hearing loss in Coch–/– mice. We show quantitatively that the pro-inflammatory component of cochlin, LCCL, is upregulated after noise exposure in perilymph of wild-type mice compared to unexposed mice, as is the enzyme catalyzing LCCL release, aggrecanase1, encoded by Adamts4. We further show that upregulation of pro-inflammatory cytokines in perilymph and cochlear soft-tissue after noise exposure is lower in cochlin knock-out than wild-type mice. Taken together, our data demonstrate for the first time that cochlin deficiency results in conductive hearing loss that protects against physiologic and molecular effects of noise trauma.

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“…Compared with monoclonal antibodies, most small molecule inhibitors of ADAMTS5 are orally bioavailable ( Shiozaki et al, 2011 ), while the specificity of small molecule inhibitors is not that exquisite. Small molecule inhibitors were selected based on the structure of the ADAMTS5 protein, and the majority of inhibitors were developed based on the catalytic metalloproteinase domain ( Shiozaki et al, 2011 ; Chockalingam et al, 2011 ; Deng et al, 2012 ; Durham et al, 2017 ; Brebion et al, 2021 ; Nuti et al, 2013 ). The zinc-binding group in the catalytic metalloproteinase domain is the distinguishing structure of these inhibitors, such as hydroxamate and carboxylate ( Shiozaki et al, 2011 ; Deng et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

ADAMTS5 in Osteoarthritis: Biological Functions, Regulatory Network, and Potential Targeting Therapies

Jiang

Lin

Zhao

et al. 2021

Front. Mol. Biosci.

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ADAMTS5 is involved in the pathogenesis of OA. As the major aggrecanase-degrading articular cartilage matrix, ADAMTS5, has been regarded as a potential target for OA treatment. We here provide an updated insight on the regulation of ADAMTS5 and newly discovered therapeutic strategies for OA. Pathophysiological and molecular mechanisms underlying articular inflammation and mechanotransduction, as well as chondrocyte hypertrophy were discussed, and the role of ADAMTS5 in each biological process was reviewed, respectively. Senescence, inheritance, inflammation, and mechanical stress are involved in the overactivation of ADAMTS5, contributing to the pathogenesis of OA. Multiple molecular signaling pathways were observed to modulate ADAMTS5 expression, namely, Runx2, Fgf2, Notch, Wnt, NF-κB, YAP/TAZ, and the other inflammatory signaling pathways. Based on the fundamental understanding of ADAMTS5 in OA pathogenesis, monoclonal antibodies and small molecule inhibitors against ADAMTS5 were developed and proved to be beneficial pre-clinically both in vitro and in vivo. Recent novel RNA therapies demonstrated potentials in OA animal models. To sum up, ADAMTS5 inhibition and its signaling pathway–based modulations showed great potential in future therapeutic strategies for OA.

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A Highly Selective Hydantoin Inhibitor of Aggrecanase-1 and Aggrecanase-2 with a Low Projected Human Dose

Cited by 13 publications

References 26 publications

Discovery of GLPG1972/S201086, a Potent, Selective, and Orally Bioavailable ADAMTS-5 Inhibitor for the Treatment of Osteoarthritis

Discovery of GLPG1972/S201086, a Potent, Selective, and Orally Bioavailable ADAMTS-5 Inhibitor for the Treatment of Osteoarthritis

Cochlin Deficiency Protects Against Noise-Induced Hearing Loss

ADAMTS5 in Osteoarthritis: Biological Functions, Regulatory Network, and Potential Targeting Therapies

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