Tularik Limited

Amgen Inc.

Jin-Long Chen

M Catherine Amaral

Ning Zhang

Juan Carlos Jaen

Bei Shan

Lawrence R McGee

Jonathan B Houze

John A Flygare

Steven L McKnight

Patrick A Baeuerle

Timothy David Cushing

Hui Tian

Steven Marc Rubenstein

Patrick C Kearney

Holger Beckmann

Shi-Chang Miao

Fabienne Charles De La Brousse

Kevin Lustig

Fabienne De La Brouse-Elwood

R Marc Learned

Lei Ling

Songzhu An

David Johnston

Fabienne C De La Brousse

M Catherine Arnaral

Paul Rafferty

Wendy Wen Zhong

The present invention provides pharmaceutical compositions and methods for the treatment of diabetes mellitus using combination therapy. The compositions relate to a compound of Formula I and an antidiabetic agent such as sulfonylureas, biguanides, glitazones, &#x3b1;-glucosidase inhibitors, potassium channel antagonists, aldose reductase inhibitors, glucagon antagonists, activators of RXR, insulin therapy or other anti-obesity agent. The methods include the administration of the combination of compound of Formula I with antidiabetic agent where the two components are delivered in a simultaneous manner, where the compound of Formula I is administered first, followed by the antidiabetic agent, as well as wherein the antidiabetic agent is delivered first followed by the compound of Formula I.

Combination therapeutic compositions

Compounds, compositions and methods are provided that are useful in the treatment or prevention of a condition or disorder mediated by an uncoupling protein. In particular, the compounds of the invention modulate the expression and/or activity of UCP3. The subject compositions are particularly useful in the treatment of obesity and type II diabetes, and associated diseases 

Bis-aryl thiazole derivatives

The invention provides natural ligands of TGR183 receptors and methods of identifying modulators of various TGR183 receptors using the ligands. Methods of using the modulators to treat diseases or disorders associated with dysfunction of the TGR183 receptor are also provided.

Receptor ligands and methods of modulating receptors

The invention provides methods and compositions for screening for pharmacological agents which regulate gene expression in mammals. An exemplary assay involves (a) contacting a mammalian cell comprising a knock-in mutant of a targeted native allele encoding a reporter of gene expression, wherein the expression of the reporter is under the control of the gene expression regulatory sequences of the native allele, with a candidate agent under conditions whereby but for the presence of the agent, the reporter is expressed at a first expression level; and, (b) measuring the expression of the reporter to obtain a second expression level, wherein a difference between the first and second expression levels indicates that the candidate agent modulates gene expression.

Cell-based drug screens for regulators of gene expression

Methods for identifying modulators of nuclear hormone receptor function comprise the steps of (a) forming a mixture comprising a nuclear hormone receptor, a peptide sensor and a candidate agent, but not a natural coactivator protein of the receptor, wherein the sensor provides direct, in vitro binding to the receptor under assay conditions; (b) measuring an agent-biased binding of the sensor to the receptor; and (c) comparing the agent-biased binding with a corresponding unbiased binding of the sensor to the receptor. In particular embodiments, the sensor comprises an amphipathic alpha helix nuclear hormone interacting domain comprising a recited nuclear hormone transcriptional coactivator motif sequence, the sensor is present at sub-micromolar concentration, the binding reaction occurs in solution, the sensor comprises a fluorescent label and the measuring step comprises detecting fluorescence polarization of the label. Reagents include labeled sensor peptides and reaction mixtures consisting essentially of nuclear hormone receptor, a peptide and a candidate agent.

Nuclear hormone receptor drug screens

The invention provides natural ligands of various receptors and methods of identifying modulators of various receptors using the ligands. Methods of using the modulators to treat diseases or disorder associated with dysfunction of the receptor are also provided.

The present invention provides pharmaceutical compositions and methods for the treatment of diabetes mellitus using combination therapy. The compositions relate to a compound of Formula I and an antidiabetic agent such as sulfonylureas, biguanides, glitazones, &agr;-glucosidase inhibitors, potassium channel antagonists, aldose reductase inhibitors, glucagon antagonists, activators of RXR, insulin therapy or other anti-obesity agent. The methods include the administration of the combination of compound of Formula I with antidiabetic agent where the two components are delivered in a simultaneous manner, where the compound of Formula I is administered first, followed by the antidiabetic agent, as well as wherein the antidiabetic agent is delivered first followed by the compound of Formula I.

Combination therapeutic compositions and method of use

Modulators of PPAR&ggr; activity are provided which are useful in pharmaceutical compositions and methods for the treatment of conditions such as type II diabetes and obesity.

PPAR&ggr; modulators

Nuclear hormone receptor fluorescence polarization assay

The invention provides methods and compositions for screening for pharmacological agents which regulate satiety, fat metabolism and/or the type II diabetes mellitus in mammals, and in particular, agents active at regulating the level of ob gene expression. An exemplary assay involves (a) contacting a mammalian adipocyte comprising a mutant of a native ob allele encoding a reporter of ob gene expression, wherein the expression of the reporter is under the control of the gene expression regulatory sequences of the native ob allele, with a candidate agent under conditions whereby but for the presence of the agent, the reporter is expressed at a first expression level; and, (b) measuring the expression of the reporter to obtain a second expression level, wherein a difference between the first and second expression levels indicates that the candidate agent modulates ob gene expression. Preferred methods include cell-based transcription assays using adipocytes from transgenic animals having a &ldquo;knock-in&rdquo; luciferase reporter at least one ob allele.

Drug screens for regulators of the expression of the obese gene

The invention provides methods and compositions relating to a novel family of UCP3 polypeptides and related nucleic acids involved in metabolic regulation. The polypeptides may be produced recombinantly from transformed host cells from the disclosed mUCP3 encoding nucleic acids or purified from mammalian cells. The invention provides isolated mUCP3 hybridization probes, knock-out/in constructs and primers capable of specifically hybridizing with the disclosed mUCP3 genes, mUCP3-specific binding agents such as specific antibodies, animals and cells modified with the subject mUCP3 nucleic acids, and methods of making and using the subject compositions in the biopharmaceutical industry.

UCP3 genes

PPAR-&ggr; modulators

Murine UCP3 polypeptides

The invention relates to regulators of UCP3 gene transcription, including novel UCP3 transcriptional promoters. UCP3 promoters are used in diagnosis and pharmaceutical development. In particular, transfected cells comprising UCP3 transcriptional regulators operably linked to a reporter are used in high-throughput pharmaceutical screens.

Growing community of inventors

San Mateo, CA, United States of America

Jin-Long Chen