The Experts below are selected from a list of 60351 Experts worldwide ranked by ideXlab platform
Nicola C. Partridge - One of the best experts on this subject based on the ideXlab platform.
-
mir 873 3p targets hdac4 to stimulate Matrix Metalloproteinase 13 expression upon parathyroid hormone exposure in rat osteoblasts
Journal of Cellular Physiology, 2020Co-Authors: Desai Malavika, Nicola C. Partridge, Srinivasan Shreya, Vembar Raj Priya, Muthukumar Rohini, Nagarajan SelvamuruganAbstract:Matrix Metalloproteinase-13 (MMP-13) plays a predominant role in endochondral bone formation and bone remodeling. Parathyroid hormone (PTH) stimulates the expression of MMP-13 via Runx2, a bone transcription factor in rat osteoblastic cells (UMR106-01), and histone deacetylase 4 (HDAC4) acts as a corepressor of Runx2. Moreover, microRNAs (miRNAs) play an important role in regulating genes posttranscriptionally. Here, we hypothesized that PTH upregulates the miRNAs targeting HDAC4, which could lead to increased Runx2 activity and MMP-13 expression in rat osteoblastic cells. We identified several miRNAs that putatively target rat HDAC4 using bioinformatics tools. miR-873-3p was significantly upregulated by PTH in rat osteoblasts. miR-873-3p overexpression downregulated HDAC4 protein expression, increased Runx2 binding at the MMP-13 promoter, and increased MMP-13 messenger RNA expression in UMR106-01 cells. A luciferase reporter assay identified the direct targeting of miR-873-3p at the 3'-untranslated region of HDAC4. Thus, miR-873-3p targeted HDAC4 and relieved the corepressor effect of HDAC4 on Runx2 for MMP-13 expression in rat osteoblasts. This study advances our knowledge of posttranscriptional gene regulation occurring in bone and bone-related diseases and clarifies the role of miRNAs as diagnostic biomarkers.
-
Parathyroid hormone-induced down-regulation of miR-532-5p for Matrix Metalloproteinase-13 expression in rat osteoblasts.
Journal of cellular biochemistry, 2018Co-Authors: Vishal Mohanakrishnan, Nicola C. Partridge, Arumugam Balasubramanian, Gokulnath Mahalingam, Ilangovan Ramachandran, Nagarajan SelvamuruganAbstract:Parathyroid hormone (PTH) acts on osteoblasts and functions as an essential regulator of calcium homeostasis and as a mediator of bone remodeling. We previously reported that PTH stimulates the expression of Matrix Metalloproteinase-13 (MMP-13) in rat osteoblasts and that MMP-13 plays a key role in bone remodeling, endochondral bone formation, and bone repair. Recent evidence indicated that microRNAs (miRNAs) have regulatory functions in bone metabolism. In this study, we hypothesized that the down-regulation of miRNAs that target MMP-13 by PTH leads to the stimulation of MMP-13 expression in osteoblasts. We used various bioinformatic tools to identify miRNAs that putatively target rat MMP-13. Among these miRNAs, the expression of miR-532-5p in rat osteoblasts decreased at 4 h of PTH-treatment, whereas MMP-13 mRNA expression was maximal at the same time point. When an miR-532-5p mimic was transiently transfected into UMR-106-01 cells, MMP-13 mRNA and protein expression decreased. Using a luciferase reporter assay system, we also identified that miR-532-5p directly targeted the 3' UTRs of MMP-13 gene. Based on these results, we suggest that PTH-induced down-regulation of miR-532-5p resulted in the stimulation of MMP-13 expression in rat osteoblasts. This study identified a significant role of miRNA in controlling bone remodeling via PTH-stimulated MMP-13 expression. This finding enhances our understanding of bone metabolism and bone-related diseases and it could provide information regarding the usage of miRNAs as therapeutic agents or biomarkers.
-
characterization of runx2 phosphorylation sites required for tgf β1 mediated stimulation of Matrix Metalloproteinase 13 expression in osteoblastic cells
Journal of Cellular Physiology, 2018Co-Authors: Balasubramanian Arumugam, Nicola C. Partridge, M Vairamani, N SelvamuruganAbstract:Transforming growth factor-beta1 (TGF-β1), a highly abundant growth factor in skeletal tissues, stimulates Matrix Metalloproteinase-13 (MMP-13) expression in osteoblastic cells. MMP-13 plays a critical role in bone remodeling. Runx2, a bone transcription factor, is required for TGF-β1-mediated stimulation of MMP-13 expression in osteoblastic cells. In this study, the molecular mechanism responsible for TGF-β1-stimulation of MMP-13 expression via Runx2 in osteoblastic cells was elucidated. TGF-β1 stimulated the phosphorylation of Runx2 at serine amino acids, and ERK inhibition blocked this effect in rat (UMR106-01) and human (MG-63) osteoblastic cells. Pretreatment with okadaic acid, a serine-threonine phosphatase inhibitor, increased Runx2 serine phosphorylation in osteoblastic cells. When cells were pretreated with an ERK inhibitor, TGF-β1-mediated stimulation of MMP-13 mRNA expression decreased. Nano-ESI/LC/MS analysis identified that TGF-β1 stimulates Runx2 phosphorylation at three serine amino acids. Transient transfection of mouse mesenchymal stem cells (C3H10T1/2) with Runx2 serine mutant constructs decreased TGF-β1-mediated Runx2 serine phosphorylation. A luciferase reporter assay identified that TGF-β1 stimulated MMP-13 promoter activity in these cells only in the presence of the wild Runx2 construct, and not with mutant Runx2. Thus, TGF-β1 stimulates the phosphorylation of Runx2 at three serine amino acids, and this event is required for MMP-13 expression in osteoblastic cells. Hence, this study contributes to the knowledge of events governing bone remodeling and bone-related diseases.
-
HDAC4 Represses Matrix Metalloproteinase-13 Transcription in Osteoblastic Cells, and Parathyroid Hormone Controls This Repression
The Journal of biological chemistry, 2010Co-Authors: Emi Shimizu, Nagarajan Selvamurugan, Jennifer J. Westendorf, Eric N. Olson, Nicola C. PartridgeAbstract:Parathyroid hormone (PTH) is a hormone regulating bone remodeling through its actions on both bone formation and bone resorption. Previously we reported that PTH induces Matrix Metalloproteinase-13 (MMP-13) transcription in osteoblastic cells. Here, we show that histone deacetylase 4 (HDAC4) interacts with Runx2, binds the MMP-13 promoter, and suppresses MMP-13 gene transcription in the rat osteoblastic cell line, UMR 106-01. PTH induces the rapid cAMP-dependent protein kinase-dependent release of HDAC4 from the MMP-13 promoter and subsequent transcription of MMP-13. Knock-out of HDAC4 either by siRNA in vitro or by gene deletion in vivo leads to an increase in MMP-13 expression, and overexpression of HDAC4 decreases the PTH induction of MMP-13. All of these observations indicate that HDAC4 represses MMP-13 gene transcription in bone. Moreover, PTH stimulates HDAC4 gene expression and enzymatic activity at times corresponding to the reassociation of HDAC4 with the MMP-13 promoter and a decline in its transcription. Thus, HDAC4 is a basal repressor of MMP-13 transcription, and PTH regulates HDAC4 to control MMP-13 promoter activity. These data identify a novel and discrete mechanism of regulating HDAC4 levels and, subsequently, gene expression.
-
Identification and characterization of Runx2 phosphorylation sites involved in Matrix Metalloproteinase-13 promoter activation
FEBS letters, 2009Co-Authors: Nagarajan Selvamurugan, Emi Shimizu, Minnkyong Lee, Tong Liu, Nicola C. PartridgeAbstract:Matrix Metalloproteinase-13 (MMP-13) plays a critical role in parathyroid hormone (PTH)-induced bone resorption. PTH acts via protein kinase A (PKA) to phosphorylate and stimulate the transactivation of Runx2 for MMP-13 promoter activation. We show here that PTH stimulated Runx2 phosphorylation in rat osteoblastic cells. Runx2 was phosphorylated on serine 28 and threonine 340 after 8-bromo cyclic adenosine mono phosphate (8-Br-cAMP) treatment. We further demonstrate that in the presence of 8-Br-cAMP, the wild-type Runx2 construct stimulated MMP-13 promoter activity, while the Runx2 construct having mutations at three phosphorylation sites (S28, S347 and T340) was unable to stimulate MMP-13 promoter activity. Thus, we have identified the Runx2 phosphorylation sites necessary for PKA stimulated MMP-13 promoter activation and this event may be critical for bone remodeling.
Nagarajan Selvamurugan - One of the best experts on this subject based on the ideXlab platform.
-
mir 873 3p targets hdac4 to stimulate Matrix Metalloproteinase 13 expression upon parathyroid hormone exposure in rat osteoblasts
Journal of Cellular Physiology, 2020Co-Authors: Desai Malavika, Nicola C. Partridge, Srinivasan Shreya, Vembar Raj Priya, Muthukumar Rohini, Nagarajan SelvamuruganAbstract:Matrix Metalloproteinase-13 (MMP-13) plays a predominant role in endochondral bone formation and bone remodeling. Parathyroid hormone (PTH) stimulates the expression of MMP-13 via Runx2, a bone transcription factor in rat osteoblastic cells (UMR106-01), and histone deacetylase 4 (HDAC4) acts as a corepressor of Runx2. Moreover, microRNAs (miRNAs) play an important role in regulating genes posttranscriptionally. Here, we hypothesized that PTH upregulates the miRNAs targeting HDAC4, which could lead to increased Runx2 activity and MMP-13 expression in rat osteoblastic cells. We identified several miRNAs that putatively target rat HDAC4 using bioinformatics tools. miR-873-3p was significantly upregulated by PTH in rat osteoblasts. miR-873-3p overexpression downregulated HDAC4 protein expression, increased Runx2 binding at the MMP-13 promoter, and increased MMP-13 messenger RNA expression in UMR106-01 cells. A luciferase reporter assay identified the direct targeting of miR-873-3p at the 3'-untranslated region of HDAC4. Thus, miR-873-3p targeted HDAC4 and relieved the corepressor effect of HDAC4 on Runx2 for MMP-13 expression in rat osteoblasts. This study advances our knowledge of posttranscriptional gene regulation occurring in bone and bone-related diseases and clarifies the role of miRNAs as diagnostic biomarkers.
-
Stimulation of ATF3 interaction with Smad4 via TGF-β1 for Matrix Metalloproteinase 13 gene activation in human breast cancer cells.
International journal of biological macromolecules, 2019Co-Authors: M. Rohini, B. Arumugam, Mariappanadar Vairamani, Nagarajan SelvamuruganAbstract:Abstract We previously reported that transforming growth factor-β1 (TGF-β1) stimulated the sustained and prolonged expression of activating transcription factor 3 (ATF3) in highly metastatic and invasive human breast cancer cells (MDA-MB231), in contrast to normal human mammary epithelial cells. However, the mechanism behind the stability of ATF3 expression is not yet known. Based on an in silico approach with co-immunoprecipitation and mass spectrometric analyses, we identified a number of proteins, including Smad4, that interacted with ATF3 after TGF-β1 treatment in MDA-MB231 cells. The knockdown of Smad4 using the siRNA technique resulted in a significant loss of ATF3 expression in these cells. Chromatin immunoprecipitation was then used to identify the formation of an ATF3 and Smad4 complex at the Matrix Metalloproteinase 13 (MMP13) promoter upon TGF-β1-treatment, and the knockdown of Smad4 decreased MMP13 promoter activity in MDA-MB231 cells. Our findings indicate that Smad4 is a pre-requisite for providing stability to ATF3 via TGF-β1 in human breast cancer cells. The targeting of Smad4 may thus provide the sustainable loss of ATF3 expression that is needed to control breast cancer progression.
-
TGF-β1-stimulation of Matrix Metalloproteinase-13 expression by down-regulation of miR-203a-5p in rat osteoblasts
International journal of biological macromolecules, 2019Co-Authors: S. Saiganesh, B. Arumugam, R. Saathvika, M. Vishal, V. Udhaya, R. Ilangovan, Nagarajan SelvamuruganAbstract:Abstract Transforming growth factor-beta1 (TGF-β1) is a pleiotropic and ubiquitous cytokine involved in bone development and bone remodeling. Matrix Metalloproteinase-13 (MMP13) plays a role in the degradation of the extracellular Matrix (ECM), and the regulation of this gene is critical in bone remodeling. We previously reported that TGF-β1 stimulates MMP13 expression in rat osteoblasts. Recently, studies have examined the regulation of bone metabolism by microRNAs (miRNAs) to determine their therapeutic potential in osteogenesis. Here, we assessed the effect of TGF-β1 on down-regulation of miRNAs that target MMP13 and stimulation of MMP13 expression in osteoblasts. We used in silico analysis and identified 11 specific miRNAs which directly target rat MMP13. Among these miRNAs, miR-203a-5p expression was significantly decreased by TGF-β1-treatment in rat osteoblasts. Transient transfection of a miR-203a-5p mimic into rat osteoblasts reduced MMP13 expression. A luciferase reporter assay confirmed a direct targeting of miR-miR-203a-5p with the 3′ untranslated regions of the MMP13 gene. Hence, we suggest that TGF-β1 stimulated down-regulation of miR-203a-5p, resulting in the stimulation of MMP13 expression in rat osteoblasts. Thus, identification of the role of miR-203a-5p via TGF-β1 and MMP13 in bone remodeling indicated its potential as a biomarker or therapeutic agent for treating bone and bone-related diseases.
-
Parathyroid hormone-induced down-regulation of miR-532-5p for Matrix Metalloproteinase-13 expression in rat osteoblasts.
Journal of cellular biochemistry, 2018Co-Authors: Vishal Mohanakrishnan, Nicola C. Partridge, Arumugam Balasubramanian, Gokulnath Mahalingam, Ilangovan Ramachandran, Nagarajan SelvamuruganAbstract:Parathyroid hormone (PTH) acts on osteoblasts and functions as an essential regulator of calcium homeostasis and as a mediator of bone remodeling. We previously reported that PTH stimulates the expression of Matrix Metalloproteinase-13 (MMP-13) in rat osteoblasts and that MMP-13 plays a key role in bone remodeling, endochondral bone formation, and bone repair. Recent evidence indicated that microRNAs (miRNAs) have regulatory functions in bone metabolism. In this study, we hypothesized that the down-regulation of miRNAs that target MMP-13 by PTH leads to the stimulation of MMP-13 expression in osteoblasts. We used various bioinformatic tools to identify miRNAs that putatively target rat MMP-13. Among these miRNAs, the expression of miR-532-5p in rat osteoblasts decreased at 4 h of PTH-treatment, whereas MMP-13 mRNA expression was maximal at the same time point. When an miR-532-5p mimic was transiently transfected into UMR-106-01 cells, MMP-13 mRNA and protein expression decreased. Using a luciferase reporter assay system, we also identified that miR-532-5p directly targeted the 3' UTRs of MMP-13 gene. Based on these results, we suggest that PTH-induced down-regulation of miR-532-5p resulted in the stimulation of MMP-13 expression in rat osteoblasts. This study identified a significant role of miRNA in controlling bone remodeling via PTH-stimulated MMP-13 expression. This finding enhances our understanding of bone metabolism and bone-related diseases and it could provide information regarding the usage of miRNAs as therapeutic agents or biomarkers.
-
HDAC4 Represses Matrix Metalloproteinase-13 Transcription in Osteoblastic Cells, and Parathyroid Hormone Controls This Repression
The Journal of biological chemistry, 2010Co-Authors: Emi Shimizu, Nagarajan Selvamurugan, Jennifer J. Westendorf, Eric N. Olson, Nicola C. PartridgeAbstract:Parathyroid hormone (PTH) is a hormone regulating bone remodeling through its actions on both bone formation and bone resorption. Previously we reported that PTH induces Matrix Metalloproteinase-13 (MMP-13) transcription in osteoblastic cells. Here, we show that histone deacetylase 4 (HDAC4) interacts with Runx2, binds the MMP-13 promoter, and suppresses MMP-13 gene transcription in the rat osteoblastic cell line, UMR 106-01. PTH induces the rapid cAMP-dependent protein kinase-dependent release of HDAC4 from the MMP-13 promoter and subsequent transcription of MMP-13. Knock-out of HDAC4 either by siRNA in vitro or by gene deletion in vivo leads to an increase in MMP-13 expression, and overexpression of HDAC4 decreases the PTH induction of MMP-13. All of these observations indicate that HDAC4 represses MMP-13 gene transcription in bone. Moreover, PTH stimulates HDAC4 gene expression and enzymatic activity at times corresponding to the reassociation of HDAC4 with the MMP-13 promoter and a decline in its transcription. Thus, HDAC4 is a basal repressor of MMP-13 transcription, and PTH regulates HDAC4 to control MMP-13 promoter activity. These data identify a novel and discrete mechanism of regulating HDAC4 levels and, subsequently, gene expression.
William R. Roush - One of the best experts on this subject based on the ideXlab platform.
-
host derived Matrix Metalloproteinase 13 activity promotes multiple myeloma induced osteolysis and reduces overall survival
Cancer Research, 2021Co-Authors: Gemma Shay, Gregg B. Fields, William R. Roush, Jun Yong Choi, Rita Fuerst, Anna M. Knapinska, Jeremy Mcguire, Kenneth H Shain, Conor C LynchAbstract:Multiple myeloma promotes systemic skeletal bone disease that greatly contributes to patient morbidity. Resorption of type-I-collagen rich bone Matrix by activated osteoclasts (OCL) results in the release of sequestered growth factors that can drive progression of the disease. Matrix Metalloproteinase-13 (MMP-13) is a collagenase expressed predominantly in the skeleton by mesenchymal stromal cells (MSC) and MSC-derived osteoblasts. Histochemical analysis of human multiple myeloma specimens also demonstrated that MMP-13 largely localizes to the stromal compartment compared to CD138+ myeloma cells. In this study, we further identified that multiple myeloma induces MMP-13 expression in bone stromal cells. Because of its ability to degrade type-I-collagen, we examined whether bone stromal derived MMP-13 contributed to myeloma progression. Multiple myeloma cells were inoculated into wild type or MMP-13 null-mice. In independent in vivo studies, MMP-13 null mice demonstrated significantly higher overall survival rates and lower levels of bone destruction compared to wild type controls. Unexpectedly, no differences in type-I-collagen processing between the groups were observed. Ex vivo stromal co-culture assays showed reduced formation and activity in MMP-13-null osteoclasts. Analysis of soluble factors from wild type and MMP-13-null MSCs revealed decreased bioavailability of various osteoclastogenic factors including CXCL7. CXCL7 was identified as a novel MMP-13 substrate and regulator of osteoclastogenesis. Underscoring the importance of host MMP-13 catalytic activity in multiple myeloma progression, we demonstrate the in vivo efficacy of a novel and highly-selective MMP-13 inhibitor that provides a translational opportunity for the treatment of this incurable disease.
-
Structure-Based Design and Synthesis of Potent and Selective Matrix Metalloproteinase 13 Inhibitors.
Journal of medicinal chemistry, 2017Co-Authors: Jun Yong Choi, Gregg B. Fields, Rita Fuerst, Anna M. Knapinska, Alexander B. Taylor, Lyndsay Smith, Xiaohang Cao, P. John Hart, William R. RoushAbstract:We describe the use of comparative structural analysis and structure-guided molecular design to develop potent and selective inhibitors (10d and (S)-17b) of Matrix Metalloproteinase 13 (MMP-13). We applied a three-step process, starting with a comparative analysis of the X-ray crystallographic structure of compound 5 in complex with MMP-13 with published structures of known MMP-13·inhibitor complexes followed by molecular design and synthesis of potent but nonselective zinc-chelating MMP inhibitors (e.g., 10a and 10b). After demonstrating that the pharmacophores of the chelating inhibitors (S)-10a, (R)-10a, and 10b were binding within the MMP-13 active site, the Zn2+ chelating unit was replaced with nonchelating polar residues that bridged over the Zn2+ binding site and reached into a solvent accessible area. After two rounds of structural optimization, these design approaches led to small molecule MMP-13 inhibitors 10d and (S)-17b, which bind within the substrate-binding site of MMP-13 and surround the c...
-
Characterization of Selective Exosite-Binding Inhibitors of Matrix Metalloproteinase 13 That Prevent Articular Cartilage Degradation in Vitro
Journal of medicinal chemistry, 2014Co-Authors: Timothy P. Spicer, Peter Hodder, Gregg B. Fields, William R. Roush, Jun Yong Choi, Alexander B. Taylor, P. John Hart, Jianwen Jiang, Dmitriy MinondAbstract:Matrix Metalloproteinase 13 (MMP-13) has been shown to be the main collagenase responsible for degradation of articular cartilage during osteoarthritis and therefore represents a target for drug development. As a result of high-throughput screening and structure–activity relationship studies, we identified a novel, highly selective class of MMP-13 inhibitors (compounds 1 (Q), 2 (Q1), and 3 (Q2)). Mechanistic characterization revealed a noncompetitive nature of these inhibitors with binding constants in the low micromolar range. Crystallographic analyses revealed two binding modes for compound 2 in the MMP-13 S1′ subsite and in an S1/S2* subsite. Type II collagen- and cartilage-protective effects exhibited by compounds 1, 2, and 3 suggested that these compounds might be efficacious in future in vivo studies. Finally, these compounds were also highly selective when tested against a panel of 30 proteases, which, in combination with a good CYP inhibition profile, suggested low off-target toxicity and drug–dru...
-
Identification of novel, exosite-binding Matrix Metalloproteinase-13 inhibitor scaffolds
Bioorganic & medicinal chemistry letters, 2011Co-Authors: Joshua Roth, Dmitriy Minond, Etzer Darout, Qin Liu, Janelle L. Lauer, Peter Hodder, Gregg B. Fields, William R. RoushAbstract:Matrix Metalloproteinase-13 (MMP-13) has been implicated as the protease responsible for collagen degradation in cartilage during osteoarthritis (OA). Compounds that inhibit the Metalloproteinase at the Zn binding site typically lack specificity among MMP family members. Analogs of the low-micromolar lead MMP-13 inhibitor 4, discovered through high-throughput screening, were synthesized to investigate structure-activity relationships in this inhibitor series. Systematic modifications of 4 led to the discovery of MMP-13 inhibitors 20 and 24 which are more selective than 4 against other MMPs. Compound 20 is also approximately fivefold more potent as an MMP-13 inhibitor than the original HTS-derived lead compound 4.
Kenneth S Kilgore - One of the best experts on this subject based on the ideXlab platform.
-
quinazolinones and pyrido 3 4 d pyrimidin 4 ones as orally active and specific Matrix Metalloproteinase 13 inhibitors for the treatment of osteoarthritis
Journal of Medicinal Chemistry, 2008Co-Authors: Joe Nahra, Adam R Johnson, Amy Mae Bunker, Patrick Michael Obrien, Wensong Yue, Daniel F Ortwine, Chiufai Man, Vijay Baragi, Kenneth S Kilgore, Richard D DyerAbstract:Quinazolinones 8 and pyrido[3,4-d]pyrimidin-4-ones 9 as orally active and specific Matrix Metalloproteinase-13 inhibitors were discovered for the treatment of osteoarthritis. Starting from a high-t...
-
Quinazolinones and Pyrido[3,4-d]pyrimidin-4-ones as Orally Active and Specific Matrix Metalloproteinase-13 Inhibitors for the Treatment of Osteoarthritis
Journal of medicinal chemistry, 2008Co-Authors: Joe Nahra, Adam R Johnson, Amy Mae Bunker, Wensong Yue, Daniel F Ortwine, Chiufai Man, Vijay Baragi, Patrick Michael O'brien, Kenneth S KilgoreAbstract:Quinazolinones 8 and pyrido[3,4-d]pyrimidin-4-ones 9 as orally active and specific Matrix Metalloproteinase-13 inhibitors were discovered for the treatment of osteoarthritis. Starting from a high-through-put screening (HTS) hit thizolopyrimidin-dione 7, we obtained two chemotypes, 8 and 9, using computer-aided drug design (CADD) and methodical structure–activity relationship (SAR) studies. They occupy the unique S1′-specificity pocket and do not bind to the Zn2+ ion. Some pyrido[3,4-d]pyrimidin-4-ones, such as 10a, possess favorable absorption, distribution, metabolism, and elimination (ADME) and safety profiles. 10a effectively prevents cartilage damage in rabbit animal models of osteoarthritis without inducing musculoskeletal side effects when given at extremely high doses to rats.
Joe Nahra - One of the best experts on this subject based on the ideXlab platform.
-
quinazolinones and pyrido 3 4 d pyrimidin 4 ones as orally active and specific Matrix Metalloproteinase 13 inhibitors for the treatment of osteoarthritis
Journal of Medicinal Chemistry, 2008Co-Authors: Joe Nahra, Adam R Johnson, Amy Mae Bunker, Patrick Michael Obrien, Wensong Yue, Daniel F Ortwine, Chiufai Man, Vijay Baragi, Kenneth S Kilgore, Richard D DyerAbstract:Quinazolinones 8 and pyrido[3,4-d]pyrimidin-4-ones 9 as orally active and specific Matrix Metalloproteinase-13 inhibitors were discovered for the treatment of osteoarthritis. Starting from a high-t...
-
Quinazolinones and Pyrido[3,4-d]pyrimidin-4-ones as Orally Active and Specific Matrix Metalloproteinase-13 Inhibitors for the Treatment of Osteoarthritis
Journal of medicinal chemistry, 2008Co-Authors: Joe Nahra, Adam R Johnson, Amy Mae Bunker, Wensong Yue, Daniel F Ortwine, Chiufai Man, Vijay Baragi, Patrick Michael O'brien, Kenneth S KilgoreAbstract:Quinazolinones 8 and pyrido[3,4-d]pyrimidin-4-ones 9 as orally active and specific Matrix Metalloproteinase-13 inhibitors were discovered for the treatment of osteoarthritis. Starting from a high-through-put screening (HTS) hit thizolopyrimidin-dione 7, we obtained two chemotypes, 8 and 9, using computer-aided drug design (CADD) and methodical structure–activity relationship (SAR) studies. They occupy the unique S1′-specificity pocket and do not bind to the Zn2+ ion. Some pyrido[3,4-d]pyrimidin-4-ones, such as 10a, possess favorable absorption, distribution, metabolism, and elimination (ADME) and safety profiles. 10a effectively prevents cartilage damage in rabbit animal models of osteoarthritis without inducing musculoskeletal side effects when given at extremely high doses to rats.