Merck Sharp + Dohme Corp.

Bristol-myers Squibb Compnay

Icagen, Inc.

Other

Merck + Co., Inc.

Harvard College

Nicox S.a.

Lin Yan

Pei Huo

Songnian Lin

Ravi P Nargund

Amjad Ali

Danqing D Feng

Dmitri A Pissarnitski

Yuping Zhu

Heather J Finlay

John E Lloyd

Michael Man-Chu Lo

Ahmet Kekec

Christina B Madsen-Duggan

Zhicai Wu

George M Whitesides

Karnail S Atwal

Jeffrey John Hale

Wayne D Vaccaro

Michael F Gross

Zhi-Cai Shi

Yoon T Jeon

Serge Beaudoin

Yingjun Mu

Rao S Bhandaru

Shrenik K Shah

Robert K Baker

Emanuele Ostuni

Timothy J Henderson

Brent Whitehead

Christopher L Franklin

Edward Metzger

Zhiqiang Guo

Brenda Pipik

Robert G Chapman

Michael N Liang

Anandan Palani

Thomas F Walsh

George A Doherty

Dong-Ming Shen

Kathleen M Rupprecht

Shuguang Zhang

Iyassu Sebhat

John S Debenham

Nicoletta Almirante

Alexander Rich

Petr Vachal

Zhiqiang Zhao

Stefano Biondi

Vincent Colandrea

Zhiqiang Yang

Christopher R Moyes

Jun Wang

Chris Moyes

David N Hunter

James Dellureficio

Alessia Nicotra

Massimiliano Ferrario

Erin N Guidry

Irene E Legiec

Leslie Toth

Joseph L Duffy

Iyassu K Sebhat

Glucose-responsive insulin conjugates that contain one or more linear oligomer sugar cluster are provided. Such insulin conjugates that may display a pharmacokinetic (PK) and/or pharmacodynamic (PD) profile that is responsive to the systemic concentrations of a saccharide such as glucose or alpha-methylmannose, even when administered to a subject in need thereof in the absence of an exogenous multivalent saccharide-binding molecule.

Glucose-responsive insulin conjugates

The present disclosure provides conjugates that comprise an insulin molecule conjugated via a conjugate framework to two or more separate ligands that each include a saccharide, wherein the framework, ligand, saccharide and insulin molecule optionally comprise a fatty chain (e.g., a C8-30 fatty chain), wherein when said insulin molecule is conjugated both to a C8-30 fatty chain and one or more separate ligands that each include a saccharide, said C8-30 fatty chain is linked to insulin molecule only, and wherein when the framework or ligand comprises a fatty chain the insulin molecule is conjugated to two or more separate ligands. In certain embodiments, a conjugate is characterized in that, when the conjugate is administered to a mammal, at least one pharmacokinetic (PK) and/or pharmacodynamic (PD) property of the conjugate is sensitive to serum concentration of a second saccharide. In certain embodiments, a conjugate is also characterized by having a protracted PK profile. Exemplary conjugates and sustained release formulations are provided in addition to methods of use and preparation.

Conjugate based systems for controlled insulin delivery

Insulin dimers conjugated to peptides having at least one incretin activity are disclosed.

Insulin dimer-incretin conjugates

An insulin conjugate comprising or consisting of a tri-valent sugar cluster is described. In particular aspects, the insulin conjugate displays a pharmacokinetic (PK) and/or pharmacodynamic (PD) profile that is responsive to the systemic concentrations of a saccharide such as glucose or alpha-methylmannose even when administered to a subject in need thereof in the absence of an exogenous multivalent saccharide-binding molecule such as Con A.

Glucose responsive insulin comprising a tri-valent sugar cluster for treatment of diabetes

Insulin dimers and insulin analog dimers that act as partial agonists at the insulin receptor are disclosed.

Insulin receptor partial agonists

Insulin conjugates comprising an insulin molecule covalently attached to at least one bi-dentate linker having two arms, each arm independently attached to a ligand comprising a saccharide and wherein the saccharide for at least one ligand of the linker is fucose are disclosed. The insulin conjugates display a pharmacokinetic (PK) and/or pharmacodynamic (PD) profile that is responsive to the systemic concentrations of a saccharide such as glucose or alpha-methylmannose even when administered to a subject in need thereof in the absence of an exogenous multivalent saccharide-binding molecule such as Con A.

Diazeniumdiolate cyclohexyl derivatives

A compound having the structure: useful for treating hypertension, Pulmonary Arterial Hypertension (PAH), congestive heart failure, conditions resulting from excessive water retention, cardiovascular disease, diabetes, oxidative stress, endothelial dysfunction, cirrhosis, pre-eclampsia, osteoporosis or nephropathy. 

Diazeniumdiolate heterocyclic derivatives

A compound of formula I, wherein R1-R7 are defined herein, or stereoisomers therof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof, and methods of using these compounds for treating hypertension.

Diazeniumdiolate cyclopentyl derivatives

A compound having the structure (I) or a pharmaceutically acceptable salt thereof, wherein Ris hydrogen, deuterium, &#x2014;OH, &#x2014;OCalkyl, or halogen; Ris hydrogen, deuterium, or Calkyl; Rand Rare independently hydrogen, &#x2014;Calkyl, &#x2014;OH, &#x2014;OCalkyl, or halogen; Rand Rare independently &#x2014;Calkyl, &#x2014;(CH)OH, or &#x2014;OCalkyl, or, together with the nitrogen atom to which they are attached, form a 4- to 7-membered heterocyclic ring containing one nitrogen atom and 0 or 1 oxygen atoms, wherein said ring is unsubstituted or mono-, di- or tri-substituted with halogen or &#x2014;Calkyl; R15 is &#x2014;C(O)OH, &#x2014;C(O)OCHCHNCH)wherein n is 0, 1 or 2, &#x2014;C(O)NHCH(R)OR, or &#x2014;C(O)NHCH(R)C(O)NHCH(R)C(O)OR; Ris hydrogen, Calkyl, or (CH)NRRR; R, R, R, R, R, R, R, R, R, R, R, R, and Rare independently hydrogen or &#x2014;Calkyl; and stereoisomers thereof, and pharmaceutically acceptable salts thereof, and pharmaceutically acceptable salts of stereoisomers thereof. 

A compound having the structure formula (I) or a pharmaceutically acceptable salt thereof, and methods of using the compounds for treating hypertension. 

Diuretics

Growing community of inventors

East Brunswick, NJ, United States of America

Lin Yan