Network


Latest external collaboration on country level. Dive into details by clicking on the dots.

Hotspot


Dive into the research topics where Christopher John Rito is active.

Publication


Featured researches published by Christopher John Rito.


Current Oncology Reports | 2002

Protein kinase C inhibitors

William F. Heath; Michael R. Jirousek; John H. McDonald; Christopher John Rito

Protein kinase C (PKC) is a family of serine-threonine protein kinases that are involved in signal transduction pathways that regulate growth factor response, proliferation, and apoptosis. Its central role in these processes, which are closely involved in tumor initiation, progression, and response to antitumor agents, makes it an attractive therapeutic target in cancer. Despite initial activity seen in melanoma (bryostatin and UCN-01), non-Hodgkin’s lymphoma (ISIS 3521, bryostatin, and UCN-01), and ovarian carcinoma (ISIS 3521 and bryostatin) in phase I studies, single-agent activity in those phase II studies reported to date has been limited. Preclinical data highlight a role for PKC in modulation of drug resistance and synergy with conventional cytotoxic drugs. A randomized phase III study of ISIS 3521 in combination with carboplatin and paclitaxel, compared with chemotherapy alone, in advanced non-small-cell lung cancer is underway. This paper reviews the rationale for using PKC inhibitors in cancer therapy, the challenges for clinical trial design, and the recent clinical experience with modulators of PKC activity.


Molecular Diversity | 1997

The use of high-throughput synthesis and purification in the preparation of a directed library of adrenergic agents

Miles Goodman Siegel; Athony J. Shuker; Christine Ann Droste; Patrick J. Hahn; Cynthia Darshini Jesudason; John H. McDonald; Donald P. Matthews; Christopher John Rito; Andrew John Thorpe

A library of potential agonists and antagonists for adrenergic receptors was prepared using high-throughput solution-phase parallel synthesis. Traditional solution-phase reductive amination reactions followed by rapid purification by ion exchange chromatography yielded products with near-analytical purity. An array of ketones and amines, arranged in an 8 × 12 matrix, were combined to form 96 individual compounds.


Osteoarthritis and Cartilage | 2010

A short-term pharmacodynamic model for monitoring aggrecanase activity: injection of monosodium iodoacetate (MIA) in rats and assessment of aggrecan neoepitope release in synovial fluid using novel ELISAs.

C.A. Swearingen; Mark Chambers; C. Lin; Jothirajah Marimuthu; Christopher John Rito; Q.L. Carter; J. Dotzlaf; C. Liu; Srinivasan Chandrasekhar; K.L. Duffin; P.G. Mitchell; Timothy B. Durham; Michael Robert Wiley; Kannan Thirunavukkarasu

OBJECTIVE To develop a short-term in vivo model in rats, with an enzyme-linked immunosorbent assay (ELISA) readout for specific aggrecanase-cleaved aggrecan fragments, to facilitate testing of aggrecanase inhibitors. METHODS Monosodium iodoacetate (MIA), a metabolic inhibitor, was injected into the right knee joint of male Lewis rats and the release of aggrecanase-cleaved fragments of aggrecan containing the NITEGE or ARGN neoepitope was measured in the synovial fluid at 7 days post MIA injection using novel ELISAs. The ELISAs utilize a commercial antibody directed against the hyaluronic-acid binding region (HABR) of aggrecan, in combination with either an alpha-NITEGE antibody (NITEGE ELISA) or an alpha-ARGS/BC3 antibody (ARGS ELISA), to detect aggrecanase-cleavage of aggrecan within the interglobular domain (IGD). Aggrecan fragments present in in vitro digests, in cytokine-treated cartilage explant culture supernatants and in rat synovial fluid lavage samples were detected and quantified using the two ELISAs. Small molecule inhibitors of aggrecanase activity were dosed orally on days 3-7 to determine their ability to inhibit MIA-induced generation of the NITEGE and ARGN neoepitopes measured in the rat synovial fluid. RESULTS The NITEGE assay was shown to specifically detect the N-terminal fragment of aggrecan comprising the G1 domain and the NITEGE neoepitope sequence. This assay can readily measure aggrecanase-cleaved bovine, human and rat aggrecan without the need for deglycosylation. The ARGS assay specifically detects C-terminal fragments of aggrecan comprising the ARGS/ARGN neoepitope and the G2 domain. Keratan sulfate (KS) residues of aggrecan interfere with this ELISA, and hence this assay works well with native rat articular cartilage aggrecan (that lacks KS residues) and with deglycosylated bovine and human aggrecan. Injection of MIA into the rat knee joints resulted in a time-dependent increase in the release of aggrecanase-cleaved aggrecan fragments into the synovial fluid and treatment with an aggrecanase inhibitor resulted in a dose-dependent inhibition of the generation of these neoepitopes. CONCLUSIONS We have established a short-term in vivo model in rats that involves measurement of synovial fluid biomarkers that are dependent on aggrecanase activity in the joint. The short duration of the model combined with the mechanistic biomarker readout makes it very useful for the initial in vivo screening of aggrecanase inhibitors prior to testing them in time and resource-intensive disease models of osteoarthritis (OA).


ACS Medicinal Chemistry Letters | 2016

Novel Autotaxin Inhibitors for the Treatment of Osteoarthritis Pain: Lead Optimization via Structure-Based Drug Design

Spencer Brian Jones; Lance Allen Pfeifer; Thomas John Bleisch; Thomas James Beauchamp; Jim D. Durbin; V. Joseph Klimkowski; Norman E. Hughes; Christopher John Rito; Yen Dao; Joseph Michael Gruber; Hai Bui; Mark Chambers; Srinivasan Chandrasekhar; C. Lin; Denis J. McCann; Daniel R. Mudra; J.L. Oskins; Craig Swearingen; Kannan Thirunavukkarasu; Bryan H. Norman

In an effort to develop a novel therapeutic agent aimed at addressing the unmet need of patients with osteoarthritis pain, we set out to develop an inhibitor for autotaxin with excellent potency and physical properties to allow for the clinical investigation of autotaxin-induced nociceptive and neuropathic pain. An initial hit identification campaign led to an aminopyrimidine series with an autotaxin IC50 of 500 nM. X-ray crystallography enabled the optimization to a lead compound that demonstrated favorable potency (IC50 = 2 nM), PK properties, and a robust PK/PD relationship.


Journal of Medicinal Chemistry | 2014

Identification of potent and selective hydantoin inhibitors of aggrecanase-1 and aggrecanase-2 that are efficacious in both chemical and surgical models of osteoarthritis.

Timothy B. Durham; Valentine J. Klimkowski; Christopher John Rito; Jothirajah Marimuthu; James Lee Toth; Chin Liu; Jim D. Durbin; Stephanie L. Stout; Lisa A. Adams; Craig Swearingen; C. Lin; Mark Chambers; Kannan Thirunavukkarasu; Michael Robert Wiley

A disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4) and ADAMTS-5 are zinc metalloproteases commonly referred to as aggrecanase-1 and aggrecanase-2, respectively. These enzymes are involved in the degradation of aggrecan, a key component of cartilage. Inhibitors of these enzymes could be potential osteoarthritis (OA) therapies. A series of hydantoin inhibitors of ADAMTS-4 and ADAMTS-5 were identified from a screening campaign and optimized through structure-based drug design to give hydantoin 13. Hydantoin 13 had excellent selectivity over other zinc metalloproteases such as TACE, MMP2, MMP3, MMP13, and MMP14. The compound also produced efficacy in both a chemically induced and surgical model of OA in rats.


Bioorganic & Medicinal Chemistry Letters | 1995

Synthesis of bisindolylmaleimide macrocycles

Michael R. Jirousek; James Ronald Gillig; David Andrew Neel; Christopher John Rito; Douglas D. O'Bannon; William F. Heath; John H. McDonald; Margaret M. Faul; Leonard L. Winneroski; Anita Melikian-Badalian; Matthew Baevsky; Larwence M Ballas; Steven E. Hall

Abstract The synthesis of a novel class of N-N′-macrocyclic bisindolylmaleimides is reported. The key step involves a remarkably efficient intramolecular cyclization reaction. The method was further developed to provide an efficient synthesis of this type of macrocycle through an intermolecular alkylation with subsequent intramolecular cyclization.


ACS Medicinal Chemistry Letters | 2011

Combination of a Beta adrenoceptor modulator and a norepinephrine-serotonin uptake inhibitor for the treatment of obesity.

Cynthia Darshini Jesudason; James E. Baker; Robert D. Bryant; Jack W. Fisher; Libbey S. O’Farrell; Gregory A. Gaich; Minxia M. He; Steven D. Kahl; Aidas Kriauciunas; Mark L. Heiman; Mary A. Peters; Christopher John Rito; Julie H. Satterwhite; Frank C. Tinsley; William G. Trankle; Anthony J. Shuker

We report the novel combination of a selective beta adrenoceptor modulator and a norepinephrine-serotonin uptake inhibitor (sibutramine) with potential for the treatment of obesity. The synthesis and characterization of 6-[4-[2-[[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]amino]-2-methylpropyl]phenoxy]pyridine-3-carboxamide (LY377604), a human β3-adrenergic receptor agonist and β1- and β2-adrenergic receptor antagonist with no sympathomimetic activity at the β1- and β2-adrenergic receptors, is reported. Some in vivo data in both rats and humans is presented.


Journal of Medicinal Chemistry | 1996

(S)-13-[(dimethylamino)methyl]-10,11,14,15-tetrahydro-4,9:16, 21-dimetheno-1H, 13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecene-1,3(2H)-d ione (LY333531) and related analogues: isozyme selective inhibitors of protein kinase C beta.

Michael R. Jirousek; James Ronald Gillig; Cecile M. Gonzalez; William F. Heath; John H. McDonald; David Andrew Neel; Christopher John Rito; Upinder Singh; Lawrence E. Stramm; Anita Melikian-Badalian; Matthew Baevsky; Lawrence M. Ballas; Leonard L. Winneroski; Margaret M. Faul


Diabetes | 2002

A Tailored Therapy for the Metabolic Syndrome The Dual Peroxisome Proliferator-Activated Receptor-α/γ Agonist LY465608 Ameliorates Insulin Resistance and Diabetic Hyperglycemia While Improving Cardiovascular Risk Factors in Preclinical Models

Garret J. Etgen; Brian A. Oldham; William T. Johnson; Carol L. Broderick; Chahrzad R. Montrose; Joseph T. Brozinick; Elizabeth A. Misener; James S. Bean; William R. Bensch; Dawn A. Brooks; Anthony J. Shuker; Christopher John Rito; James R. McCarthy; Robert Ardecky; John S. Tyhonas; Sharon L. Dana; James M. Bilakovics; James R. Paterniti; Kathleen M. Ogilvie; Sha Liu; Raymond F. Kauffman


Archive | 2002

Modulators of peroxisome proliferator activated receptors

Dawn A. Brooks; Christopher John Rito; Anthony J. Shuker; Samuel J. Dominianni; Alan M. Warshawsky; Lynn S. Gossett; Donald P. Matthews; David A. Hay; Robert J. Ardecky; Pierre-Yves Michellys; John S. Tyhonas

Collaboration


Dive into the Christopher John Rito's collaboration.

Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Researchain Logo
Decentralizing Knowledge