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Dive into the research topics where Shichang Miao is active.

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Featured researches published by Shichang Miao.


Annals of the Rheumatic Diseases | 2013

Chemokine receptor CCR1 antagonist CCX354-C treatment for rheumatoid arthritis: CARAT-2, a randomised, placebo controlled clinical trial

Paul P. Tak; A. Balanescu; Vira Tseluyko; Silvia Bojin; Edit Drescher; Dan Dairaghi; Shichang Miao; Vittorio Marchesin; Juan C. Jaen; Thomas J. Schall; Pirow Bekker

Objectives CCX354-C is a specific, orally administered antagonist of the C-C chemokine receptor 1, which regulates migration of monocytes and macrophages to synovial tissue. This clinical trial evaluated the safety and efficacy of CCX354-C in patients with rheumatoid arthritis (RA). Methods CARAT-2 is a 12-week double-blind, randomised, placebo controlled trial in 160 patients with RA, with 68 tender joint count and 66 swollen joint count ≥8 and C-reactive protein (CRP) >5 mg/l, despite being on methotrexate for at least 16 weeks. Subjects received placebo, CCX354-C 100 mg twice daily, or 200 mg once daily for 12 weeks. Endpoints included safety (primary) and RA disease activity assessments based on American College of Rheumatology (ACR) response, and changes in 28-joint disease activity score–CRP, individual ACR components, as well as soluble bone turnover markers. Results CCX354-C was generally well tolerated by study subjects. The ACR20 response at week 12 was 39% in the placebo group, 43% in the 100 mg twice daily group (difference and 95% CI compared with placebo, 4.5 (−14.1 to 23.1); p=0.62) and 52% in the 200 mg once daily group (13.0 (−5.8 to 31.8); p=0.17) in the intention-to-treat population, and 30% in the placebo group, 44% in the 100 mg twice daily group (14.4 (−5.9 to 34.8); p=0.17), and 56% in the 200 mg once daily group (25.8 (5.3 to 46.4); p=0.01) in the prespecified population of patients satisfying CRP and joint count eligibility criteria at the screening and day 1 (predose) visits. Conclusions CCX354-C exhibited a good safety and tolerability profile and evidence of clinical activity in RA.


Blood | 2012

CCR1 blockade reduces tumor burden and osteolysis in vivo in a mouse model of myeloma bone disease

Daniel J. Dairaghi; Babatunde O. Oyajobi; Anjana Gupta; Brandon McCluskey; Shichang Miao; Jay P. Powers; Lisa C. Seitz; Yu Wang; Yibin Zeng; Penglie Zhang; Thomas J. Schall; Juan C. Jaen

The chemokine CCL3/MIP-1α is a risk factor in the outcome of multiple myeloma (MM), particularly in the development of osteolytic bone disease. This chemokine, highly overexpressed by MM cells, can signal mainly through 2 receptors, CCR1 and CCR5, only 1 of which (CCR1) is responsive to CCL3 in human and mouse osteoclast precursors. CCR1 activation leads to the formation of osteolytic lesions and facilitates tumor growth. Here we show that formation of mature osteoclasts is blocked by the highly potent and selective CCR1 antagonist CCX721, an analog of the clinical compound CCX354. We also show that doses of CCX721 selected to completely inhibit CCR1 produce a profound decrease in tumor burden and osteolytic damage in the murine 5TGM1 model of MM bone disease. Similar effects were observed when the antagonist was used prophylactically or therapeutically, with comparable efficacy to that of zoledronic acid. 5TGM1 cells were shown to express minimal levels of CCR1 while secreting high levels of CCL3, suggesting that the therapeutic effects of CCX721 result from CCR1 inhibition on non-MM cells, most likely osteoclasts and osteoclast precursors. These results provide a strong rationale for further development of CCR1 antagonists for the treatment of MM and associated osteolytic bone disease.


Bioorganic & Medicinal Chemistry Letters | 2008

Discovery and Initial SAR of Arylsulfonylpiperazine Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1)

Daqing Sun; Zhulun Wang; Yongmei Di; Juan C. Jaen; Marc Labelle; Ji Ma; Shichang Miao; Athena Sudom; Liang Tang; Craig Tomooka; Hua Tu; Stefania Ursu; Nigel Walker; Xuelei Yan; Qiuping Ye; Jay P. Powers

High-throughput screening of a small-molecule compound library resulted in the identification of a series of arylsulfonylpiperazines that are potent and selective inhibitors of human 11beta-Hydroxysteroid Dehydrogenase Type 1 (11beta-HSD1). Optimization of the initial lead resulted in the discovery of compound (R)-45 (11beta-HSD1 IC(50)=3nM).


Bioorganic & Medicinal Chemistry Letters | 2009

Imidazo-pyrazine derivatives as potent CXCR3 antagonists

Xiaohui Du; Darin Gustin; Xiaoqi Chen; Jason Duquette; Lawrence R. McGee; Zhulun Wang; Karen Ebsworth; Kirk Henne; Bryan Lemon; Ji Ma; Shichang Miao; Emmanuel Sabalan; Timothy J. Sullivan; George Tonn; Tassie L. Collins; Julio C. Medina

A general way of improving the potency of CXCR3 antagonists with fused hetero-bicyclic cores was identified. Optimization efforts led to the discovery of a series of imidazo-pyrazine derivatives with improved pharmacokinetic properties in addition to increased potency. The efficacy of the lead compound 21 is evaluated in a mouse lung inflammation model.


Bioorganic & Medicinal Chemistry | 2013

Discovery of INT131: A selective PPARγ modulator that enhances insulin sensitivity

Joshua P. Taygerly; Lawrence R. McGee; Steven M. Rubenstein; Jonathan B. Houze; Timothy D. Cushing; Yang Li; Alykhan Motani; Jin-Long Chen; Walter Frankmoelle; Guosen Ye; Marc Learned; Juan C. Jaen; Shichang Miao; Pieter B. M. W. M. Timmermans; Martin J. Thoolen; Patrick C. Kearney; John A. Flygare; Holger Beckmann; Jennifer Weiszmann; Michelle Lindstrom; Nigel Walker; Jinsong Liu; Donna H.T. Biermann; Zhulun Wang; Atsushi Hagiwara; Tetsuya Iida; Hisateru Aramaki; Yuki Kitao; Hisashi Shinkai; Noboru Furukawa

PPARγ is a member of the nuclear hormone receptor family and plays a key role in the regulation of glucose homeostasis. This Letter describes the discovery of a novel chemical class of diarylsulfonamide partial agonists that act as selective PPARγ modulators (SPPARγMs) and display a unique pharmacological profile compared to the thiazolidinedione (TZD) class of PPARγ full agonists. Herein we report the initial discovery of partial agonist 4 and the structure-activity relationship studies that led to the selection of clinical compound INT131 (3), a potent PPARγ partial agonist that displays robust glucose-lowering activity in rodent models of diabetes while exhibiting a reduced side-effects profile compared to marketed TZDs.


Journal of diabetes & metabolism | 2012

Orally-Administered Chemokine Receptor CCR2 Antagonist CCX140-B in Type 2 Diabetes: A Pilot Double-Blind, Randomized Clinical Trial

Markolf Hanefeld; Ernest Schell; Ioanna Gouni-Berthold; Martin Melichar; Ivana Vesela; Daniel Johnson; Shichang Miao; Timothy J. Sullivan; Juan C. Jaen; Thomas J. Schall; Pirow Bekker

Study background: Inflammatory macrophages expressing the C-C chemokine receptor 2 (CCR2) accumulate in adipose tissue and contribute to insulin resistance. CCX140-B is an orally-administered antagonist of CCR2 expressed on monocytes and macrophages and blocks infiltration of these cells into adipose tissue. A pilot Phase 2 clinical trial was conducted in patients with type 2 diabetes with the primary objective to evaluate the safety and tolerability of CCX140-B. Key secondary objectives included assessment of glycemic parameters, fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c). Methods: This is a randomized, double-blind, clinical trial of CCX140-B in 159 subjects with type 2 diabetes on stable metformin for at least 8 weeks prior to study entry. HbA 1c was 6.5 to 10% and FPG 135 to 270 mg/dL at study entry. Randomized subjects received double-blind placebo (N=32), 5 mg CCX140-B (N=63), 10 mg CCX140-B (N=32), or pioglitazone 30 mg (N=32) once daily orally for 4 weeks, with a 4-week follow-up period. Results: CCX140-B was well tolerated. No serious adverse events occurred with CCX140-B. FPG showed a CCX140-B dose-dependent decrease, with 10 mg CCX140-B showing a similar decrease to pioglitazone (leastsquares mean change at week 4 of -16.1 vs. -21.4 mg/dL, respectively). HbA 1c least-squares mean changes from baseline to week 4 for the placebo, 5 mg CCX140-B, 10 mg CCX140-B, and pioglitazone groups were -0.09%, -0.09%, -0.23% (p=0.045 vs. placebo), and -0.13% (NS vs. placebo), respectively. No detrimental changes were seen in plasma monocyte chemoattractant protein-1 or blood monocyte counts with CCX140-B. Conclusion: CCX140-B, an orally administered, specific CCR2 antagonist was found to be well tolerated and safe in this Phase 2 clinical trial and showed evidence of a beneficial effect on glycemic parameters. If confirmed, CCX140-B might be beneficial in treatment of patients with type 2 diabetes. (Clinical Trial Registry: clinicaltrials.gov identifier NCT01028963).


Bioorganic & Medicinal Chemistry Letters | 2010

The synthesis and SAR of novel diarylsulfone 11β-HSD1 inhibitors.

Xuelei Yan; Zhulun Wang; Athena Sudom; Mario G. Cardozo; Michael DeGraffenreid; Yongmei Di; Pingchen Fan; Xiao He; Juan C. Jaen; Marc Labelle; Jinsong Liu; Ji Ma; Dustin L. McMinn; Shichang Miao; Daqing Sun; Liang Tang; Hua Tu; Stefania Ursu; Nigel Walker; Qiuping Ye; Jay P. Powers

In this communication, human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitory activities of a novel series of diarylsulfones are described. Optimization of this series resulted in several highly potent 11β-HSD1 inhibitors with excellent pharmacokinetic (PK) properties. Compound (S)-25 showed excellent efficacy in a non-human primate ex vivo pharmacodynamic model.


Journal of Medicinal Chemistry | 2014

Discovery of 6-phenylpyrimido[4,5-b][1,4]oxazines as potent and selective acyl CoA:diacylglycerol acyltransferase 1 (DGAT1) inhibitors with in vivo efficacy in rodents.

Brian M. Fox; Kazuyuki Sugimoto; Kiyosei Iio; Atsuhito Yoshida; Jian Zhang; Kexue Li; Xiaolin Hao; Marc Labelle; Marie-Louise Smith; Steven M. Rubenstein; Guosen Ye; Dustin Mcminn; Simon Jackson; Rebekah Choi; Bei Shan; Ji Ma; Shichang Miao; Takuya Matsui; Nobuya Ogawa; Masahiro Suzuki; Akio Kobayashi; Hidekazu Ozeki; Chihiro Okuma; Yukihito Ishii; Daisuke Tomimoto; Noboru Furakawa; Masahiro Tanaka; Mutsuyoshi Matsushita; Mitsuru Takahashi; Takashi Inaba

The discovery and optimization of a series of acyl CoA:diacylglycerol acyltransferase 1 (DGAT1) inhibitors based on a pyrimido[4,5-b][1,4]oxazine scaffold is described. The SAR of a moderately potent HTS hit was investigated resulting in the discovery of phenylcyclohexylacetic acid 1, which displayed good DGAT1 inhibitory activity, selectivity, and PK properties. During preclinical toxicity studies a metabolite of 1 was observed that was responsible for elevating the levels of liver enzymes ALT and AST. Subsequently, analogues were synthesized to preclude the formation of the toxic metabolite. This effort resulted in the discovery of spiroindane 42, which displayed significantly improved DGAT1 inhibition compared to 1. Spiroindane 42 was well tolerated in rodents in vivo, demonstrated efficacy in an oral triglyceride uptake study in mice, and had an acceptable safety profile in preclinical toxicity studies.


Bioorganic & Medicinal Chemistry Letters | 2009

Synthesis and optimization of arylsulfonylpiperazines as a novel class of inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)

Daqing Sun; Zhulun Wang; Mario G. Cardozo; Rebekah Choi; Michael DeGraffenreid; Yongmei Di; Xiao He; Juan C. Jaen; Marc Labelle; Jinsong Liu; Ji Ma; Shichang Miao; Athena Sudom; Liang Tang; Hua Tu; Stefania Ursu; Nigel Walker; Xuelei Yan; Qiuping Ye; Jay P. Powers

The synthesis and SAR of a series of arylsulfonylpiperazine inhibitors of 11beta-HSD1 are described. Optimization rapidly led to potent, selective, and orally bioavailable inhibitors demonstrating efficacy in a cynomolgus monkey ex vivo enzyme inhibition model.


PLOS ONE | 2016

Characterization of Pharmacologic and Pharmacokinetic Properties of CCX168, a Potent and Selective Orally Administered Complement 5a Receptor Inhibitor, Based on Preclinical Evaluation and Randomized Phase 1 Clinical Study.

Pirow Bekker; Daniel J. Dairaghi; Lisa Seitz; Manmohan Reddy Leleti; Yu Wang; Linda Ertl; Trageen Baumgart; Sarah Shugarts; Lisa Lohr; Ton Dang; Shichang Miao; Yibin Zeng; Pingchen Fan; Penglie Zhang; Daniel J. Johnson; Jay P. Powers; Juan C. Jaen; Israel F. Charo; Thomas J. Schall

The complement 5a receptor has been an attractive therapeutic target for many autoimmune and inflammatory disorders. However, development of a selective and potent C5aR antagonist has been challenging. Here we describe the characterization of CCX168 (avacopan), an orally administered selective and potent C5aR inhibitor. CCX168 blocked the C5a binding, C5a-mediated migration, calcium mobilization, and CD11b upregulation in U937 cells as well as in freshly isolated human neutrophils. CCX168 retains high potency when present in human blood. A transgenic human C5aR knock-in mouse model allowed comparison of the in vitro and in vivo efficacy of the molecule. CCX168 effectively blocked migration in in vitro and ex vivo chemotaxis assays, and it blocked the C5a-mediated neutrophil vascular endothelial margination. CCX168 was effective in migration and neutrophil margination assays in cynomolgus monkeys. This thorough in vitro and preclinical characterization enabled progression of CCX168 into the clinic and testing of its safety, tolerability, pharmacokinetic, and pharmacodynamic profiles in a Phase 1 clinical trial in 48 healthy volunteers. CCX168 was shown to be well tolerated across a broad dose range (1 to 100 mg) and it showed dose-dependent pharmacokinetics. An oral dose of 30 mg CCX168 given twice daily blocked the C5a-induced upregulation of CD11b in circulating neutrophils by 94% or greater throughout the entire day, demonstrating essentially complete target coverage. This dose regimen is being tested in clinical trials in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis. Trial Registration ISRCTN registry with trial ID ISRCTN13564773.

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John A. Flygare

Colorado State University

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