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Dive into the research topics where Claire M. Steppan is active.

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Featured researches published by Claire M. Steppan.


Regulatory Peptides | 2000

Leptin is a potent stimulator of bone growth in ob/ob mice

Claire M. Steppan; D. Todd Crawford; Kristen L. Chidsey-Frink; H.Z. Ke; Andrew G. Swick

Leptin, the product of the obese gene, is a circulating hormone secreted primarily from adipocytes. The lack of leptin in ob/ob mice, who are homozygous for the obese gene, results in hyperglycemia, hyperinsulinemia, hyperphagia, obesity, infertility, decreased brain size and decreased stature. To this end, we investigated the role of leptin as a hormonal regulator of bone growth. Leptin administration led to a significant increase in femoral length, total body bone area, bone mineral content and bone density in ob/ob mice as compared to vehicle treated controls. The increase in total body bone mass was a result of an increase in both trabecular and cortical bone mass. These results suggest that the decreased stature of the ob/ob mouse is due to a developmental defect that is readily reversible upon leptin administration. Our demonstration that the signalling or long form (Ob-Rb) of the leptin receptor is present in both primary adult osteoblasts and chondrocytes suggests that the growth promoting effects of leptin could be direct. In summary, these results indicate a novel role for leptin in skeletal bone growth and development.


Journal of Medicinal Chemistry | 2011

Discovery of a Clinical Candidate from the Structurally Unique Dioxa-bicyclo[3.2.1]octane Class of Sodium-Dependent Glucose Cotransporter 2 Inhibitors

Vincent Mascitti; Tristan S. Maurer; Ralph P. Robinson; Jianwei Bian; Carine M. Boustany-Kari; Thomas A. Brandt; Benjamin Micah Collman; Amit S. Kalgutkar; Michelle K. Klenotic; Michael T. Leininger; André Lowe; Robert John Maguire; Victoria M. Masterson; Zhuang Miao; Emi Mukaiyama; Jigna D. Patel; John C. Pettersen; Cathy Préville; Brian Samas; Li She; Zhanna Sobol; Claire M. Steppan; Benjamin D. Stevens; Benjamin A. Thuma; Meera Tugnait; Dongxiang Zeng; Tong Zhu

Compound 4 (PF-04971729) belongs to a new class of potent and selective sodium-dependent glucose cotransporter 2 inhibitors incorporating a unique dioxa-bicyclo[3.2.1]octane (bridged ketal) ring system. In this paper we present the design, synthesis, preclinical evaluation, and human dose predictions related to 4. This compound demonstrated robust urinary glucose excretion in rats and an excellent preclinical safety profile. It is currently in phase 2 clinical trials and is being evaluated for the treatment of type 2 diabetes.


Science Translational Medicine | 2015

Developing predictive assays: The phenotypic screening “rule of 3”

Fabien Vincent; Paula M. Loria; Marko Pregel; Robert Stanton; Linda Kitching; Karl Nocka; Regis Doyonnas; Claire M. Steppan; Adam M. Gilbert; Thomas Schroeter; Marie-Claire Peakman

Not all phenotypic assays are created equal; critically evaluating the disease relevance of the assay system, stimulus, and readout can help design the most predictive ones. Phenotypic drug discovery approaches can positively affect the translation of preclinical findings to patients. However, not all phenotypic assays are created equal. A critical question then follows: What are the characteristics of the optimal assays? We analyze this question and propose three specific criteria related to the disease relevance of the assay—system, stimulus, and end point—to help design the most predictive phenotypic assays.


Bioorganic & Medicinal Chemistry Letters | 2010

C-Aryl glycoside inhibitors of SGLT2: Exploration of sugar modifications including C-5 spirocyclization

Ralph P. Robinson; Vincent Mascitti; Carine M. Boustany-Kari; Christopher L. Carr; Patrick M. Foley; Emi Kimoto; Michael T. Leininger; André Lowe; Michelle K. Klenotic; James I. MacDonald; Robert John Maguire; Victoria M. Masterson; Tristan S. Maurer; Zhuang Miao; Jigna D. Patel; Cathy Préville; Matthew R. Reese; Li She; Claire M. Steppan; Benjamin A. Thuma; Tong Zhu

Modifications to the sugar portion of C-aryl glycoside sodium glucose transporter 2 (SGLT2) inhibitors were explored, including systematic deletion and modification of each of the glycoside hydroxyl groups. Based on results showing activity to be quite tolerant of structural change at the C-5 position, a series of novel C-5 spiro analogues was prepared. Some of these analogues exhibit low nanomolar potency versus SGLT2 and promote urinary glucose excretion (UGE) in rats. However, due to sub-optimal pharmacokinetic parameters (in particular half-life), predicted human doses did not meet criteria for further advancement.


Bioorganic & Medicinal Chemistry Letters | 2011

N-benzylimidazole carboxamides as potent, orally active stearoylCoA desaturase-1 inhibitors.

Karen Atkinson; Elena E. Beretta; Janice A. Brown; Mayda Castrodad; Yue Chen; Judith M. Cosgrove; Ping Du; John Litchfield; Michael Raymond Groton Makowski; Kelly A. Martin; Thomas J. McLellan; Constantin Neagu; David Austen Perry; David W. Piotrowski; Claire M. Steppan; Richard V. Trilles

A potent, small molecule inhibitor with a favorable pharmacokinetic profile to allow for sustained SCD inhibition in vivo was identified. Starting from a low MW acyl guanidine (5a), identified with a RapidFire High-Throughput Mass Spectrometry (RF-MS) assay, iterative library design was used to rapidly probe the amide and tail regions of the molecule. Singleton synthesis was used to probe core changes. Biological evaluation of a SCD inhibitor (5b) included in vitro potency at SCD-1 and in vivo modulation of the plasma desaturation index (DI) in rats on a low essential fatty acid (LEFA) diet. In addition to dose-dependent decrease in DI, effects on rodent ocular tissue were noted. Therefore, in rat, these SCD inhibitors only recapitulate a portion of phenotype exhibited by the SCD-1 knockout mouse.


American Journal of Physiology-gastrointestinal and Liver Physiology | 2013

Pharmacological inhibition to examine the role of DGAT1 in dietary lipid absorption in rodents and humans

Benjamin S. Maciejewski; Jennifer L. LaPerle; Danny Chen; Avijit Ghosh; William J. Zavadoski; Thomas S. McDonald; Tara B. Manion; Dawn Mather; Terrell A. Patterson; Maya Hanna; Steven Watkins; E. Michael Gibbs; Roberto A. Calle; Claire M. Steppan

Alterations in fat metabolism, in particular elevated plasma concentrations of free fatty acids and triglycerides (TG), have been implicated in the pathogenesis of Type 2 diabetes, obesity, and cardiovascular disease. Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1), a member of the large family of membrane-bound O-acyltransferases, catalyzes the final step in triacylglycerol formation. In the intestine, DGAT1 is one of the acyltransferases responsible for the reesterficiation of dietary TG. Following a single dose of a selective pharmacological inhibitor of DGAT1, PF-04620110, a dose-dependent inhibition of TG and vitamin A absorption postprandially was demonstrated in rodents and human subjects. In C57/BL6J mice, acute DGAT1 inhibition alters the temporal and spatial pattern of dietary lipid absorption. To understand the impact of DGAT1 inhibition on enterocyte lipid metabolism, lipomic profiling was performed in rat intestine and plasma as well as human plasma. DGAT1 inhibition causes an enrichment of polyunsaturated fatty acids within the TG class of lipids. This pharmacological intervention gives us insight as to the role of DGAT1 in human dietary lipid absorption.


PLOS ONE | 2011

Modeling the Mechanism of Action of a DGAT1 Inhibitor Using a Causal Reasoning Platform

Ahmed Enayetallah; Daniel Ziemek; Michael T. Leininger; Ranjit Randhawa; Jianxin Yang; Tara B. Manion; Dawn Mather; William J. Zavadoski; Max Kuhn; Judith L. Treadway; Shelly Ann G. des Etages; E. Michael Gibbs; Nigel Greene; Claire M. Steppan

Triglyceride accumulation is associated with obesity and type 2 diabetes. Genetic disruption of diacylglycerol acyltransferase 1 (DGAT1), which catalyzes the final reaction of triglyceride synthesis, confers dramatic resistance to high-fat diet induced obesity. Hence, DGAT1 is considered a potential therapeutic target for treating obesity and related metabolic disorders. However, the molecular events shaping the mechanism of action of DGAT1 pharmacological inhibition have not been fully explored yet. Here, we investigate the metabolic molecular mechanisms induced in response to pharmacological inhibition of DGAT1 using a recently developed computational systems biology approach, the Causal Reasoning Engine (CRE). The CRE algorithm utilizes microarray transcriptomic data and causal statements derived from the biomedical literature to infer upstream molecular events driving these transcriptional changes. The inferred upstream events (also called hypotheses) are aggregated into biological models using a set of analytical tools that allow for evaluation and integration of the hypotheses in context of their supporting evidence. In comparison to gene ontology enrichment analysis which pointed to high-level changes in metabolic processes, the CRE results provide detailed molecular hypotheses to explain the measured transcriptional changes. CRE analysis of gene expression changes in high fat habituated rats treated with a potent and selective DGAT1 inhibitor demonstrate that the majority of transcriptomic changes support a metabolic network indicative of reversal of high fat diet effects that includes a number of molecular hypotheses such as PPARG, HNF4A and SREBPs. Finally, the CRE-generated molecular hypotheses from DGAT1 inhibitor treated rats were found to capture the major molecular characteristics of DGAT1 deficient mice, supporting a phenotype of decreased lipid and increased insulin sensitivity.


Journal of Medicinal Chemistry | 2018

Design and Synthesis of Clinical Candidate PF-06751979: A Potent, Brain Penetrant, β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitor Lacking Hypopigmentation

Brian T. O’Neill; Elizabeth Mary Beck; Christopher Ryan Butler; Charles E. Nolan; Cathleen Gonzales; Lei Zhang; Shawn D. Doran; Kimberly Lapham; Leanne M. Buzon; Jason K. Dutra; Gabriela Barreiro; Xinjun Hou; Luis Martinez-Alsina; Bruce N. Rogers; Anabella Villalobos; John C. Murray; Kevin Ogilvie; Erik LaChapelle; Cheng Chang; Lorraine Lanyon; Claire M. Steppan; Ashley Robshaw; Katherine Hales; Germaine Boucher; Karamjeet Pandher; Christopher Houle; Claude Ambroise; David Karanian; David Riddell; Kelly R. Bales

A major challenge in the development of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors for the treatment of Alzheimers disease is the alignment of potency, drug-like properties, and selectivity over related aspartyl proteases such as Cathepsin D (CatD) and BACE2. The potential liabilities of inhibiting BACE2 chronically have only recently begun to emerge as BACE2 impacts the processing of the premelanosome protein (PMEL17) and disrupts melanosome morphology resulting in a depigmentation phenotype. Herein, we describe the identification of clinical candidate PF-06751979 (64), which displays excellent brain penetration, potent in vivo efficacy, and broad selectivity over related aspartyl proteases including BACE2. Chronic dosing of 64 for up to 9 months in dog did not reveal any observation of hair coat color (pigmentation) changes and suggests a key differentiator over current BACE1 inhibitors that are nonselective against BACE2 in later stage clinical development.


World Journal of Gastrointestinal Pathophysiology | 2017

Pharmacological inhibition of diacylglycerol acyltransferase-1 and insights into postprandial gut peptide secretion

Benjamin S. Maciejewski; Tara B. Manion; Claire M. Steppan

AIM To examine the role that enzyme Acyl-CoA:diacylglycerol acyltransferase-1 (DGAT1) plays in postprandial gut peptide secretion and signaling. METHODS The standard experimental paradigm utilized to evaluate the incretin response was a lipid challenge. Following a lipid challenge, plasma was collected via cardiac puncture at each time point from a cohort of 5-8 mice per group from baseline at time zero to 10 h. Incretin hormones [glucagon like peptide-1 (GLP-1), peptide tyrosine-tyrosine (PYY) and glucose dependent insulinotropic polypeptide (GIP)] were then quantitated. The impact of pharmacological inhibition of DGAT1 on the incretin effect was evaluated in WT mice. Additionally, a comparison of loss of DGAT1 function either by genetic ablation or pharmacological inhibition. To further elucidate the pathways and mechanisms involved in the incretin response to DGAT1 inhibition, other interventions [inhibitors of dipeptidyl peptidase-IV (sitagliptin), pancreatic lipase (Orlistat), GPR119 knockout mice] were evaluated. RESULTS DGAT1 deficient mice and wildtype C57/BL6J mice were lipid challenged and levels of both active and total GLP-1 in the plasma were increased. This response was further augmented with DGAT1 inhibitor PF-04620110 treated wildtype mice. Furthermore, PF-04620110 was able to dose responsively increase GLP-1 and PYY, but blunt GIP at all doses of PF-04620110 during lipid challenge. Combination treatment of PF-04620110 and Sitagliptin in wildtype mice during a lipid challenge synergistically enhanced postprandial levels of active GLP-1. In contrast, in a combination study with Orlistat, the ability of PF-04620110 to elicit an enhanced incretin response was abrogated. To further explore this observation, GPR119 knockout mice were evaluated. In response to a lipid challenge, GPR119 knockout mice exhibited no increase in active or total GLP-1 and PYY. However, PF-04620110 was able to increase total GLP-1 and PYY in GPR119 knockout mice as compared to vehicle treated wildtype mice. CONCLUSION Collectively, these data provide some insight into the mechanism by which inhibition of DGAT1 enhances intestinal hormone release.


Drug Metabolism and Disposition | 2018

Human Pluripotent Stem Cell–Derived Kidney Model for Nephrotoxicity Studies

Piyush Bajaj; A. David Rodrigues; Claire M. Steppan; Sandra J. Engle; Sumathy Mathialagan; Thomas Schroeter

Current in vitro models for identifying nephrotoxins are poorly predictive. We differentiated human pluripotent stem cells (hPSCs) into three-dimensional, multicellular structures containing proximal tubule cells (PTCs) and podocytes and evaluated them as a platform for predicting nephrotoxicity. The PTCs showed megalin-dependent, cubilin-mediated endocytosis of fluorescently labeled dextran and active gamma-glutamyl transpeptidase enzymes. Transporters from both the ATP-binding cassette (ABC) and the solute carrier (SLC) families were present at physiological levels in the differentiated cells, but important renal transporters such as organic anion transporter 1 (OAT1), OAT3, and organic cation transporter 2 (OCT2) were present only at lower levels. Radioactive uptake studies confirmed the functional activity of organic cation transporter, novel, type 2 (OCTN2), organic anion transporter polypeptide 4C1 (OATP4C1), and OCTs/multidrug and toxin extrusion proteins (MATEs). When treated with 10 pharmacologic agents as a test of the platform, the known nephrotoxic compounds were distinguished from the more benign compounds by an increase in tubular (PTC, kidney injury molecule 1 (KIM-1), and heme oxygenase 1 (HO-1)) and glomerular (nephrin [NPHS1]/Wilms tumor protein [WT1]) markers associated with nephrotoxicity, and we were able to distinguish the type of nephrotoxin by examining the relative levels of these markers. Given the functions demonstrated and with improved expression of key renal transporters, this hPSC-derived in vitro kidney model shows promise as a platform for detection of mechanistically different nephrotoxins.

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