Merck Sharp + Dohme Corp.

Other

Merck + Co., Inc.

Nicox S.a.

Pei Huo

Lin Yan

Ravi P Nargund

Songnian Lin

Danqing D Feng

Dmitri A Pissarnitski

Ahmet Kekec

Yuping Zhu

Christina B Madsen-Duggan

Zhicai Wu

Amjad Ali

Zhi-Cai Shi

Yingjun Mu

Jeffrey John Hale

Christopher L Franklin

Anandan Palani

Thomas F Walsh

George A Doherty

Dong-Ming Shen

Kathleen M Rupprecht

Michael Man-Chu Lo

Iyassu Sebhat

Robert K Baker

John S Debenham

Nicoletta Almirante

Petr Vachal

Zhiqiang Zhao

Stefano Biondi

Vincent Colandrea

Zhiqiang Yang

Christopher R Moyes

Chris Moyes

Brenda Pipik

David N Hunter

Erin N Guidry

Massimiliano Ferrario

Alessia Nicotra

Irene E Legiec

Leslie Toth

Joseph L Duffy

Iyassu K Sebhat

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.

Glucose-responsive insulin conjugates

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. 

Diazeniumdiolate cyclohexyl derivatives

A compound having the structure (I) wherein R is selected from the group consisting of 1) and 2), or a pharmaceutically acceptable salt thereof, and methods of using the compounds for treating hypertension. 

Diuretics

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

Cicletanine derivatives

Novel compounds of the structural formula (I) are antagonists and/or inverse agonists of the Cannabinoid-1 (CB1) receptor and are useful in the treatment, prevention and suppression of diseases mediated by the CB1 receptor. The compounds of the present invention are useful as centrally acting drugs in the treatment of psychosis, memory deficits, cognitive disorders, Alzheimer's disease, migraine, neuropathy, neuro-inflammatory disorders including multiple sclerosis and Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, and head trauma, anxiety disorders, stress, epilepsy, Parkinson's disease, Huntington's disease movement disorders, and schizophrenia. The compounds are also useful for the treatment of substance abuse disorders, the treatment of obesity or eating disorders, as well as the treatment of asthma, constipation, chronic intestinal pseudo-obstruction, cirrhosis of the liver, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and the promotion of wakefulness.

Substituted pyrano[2,3-B]pyridine derivatives as cannabinoid-1 receptor modulators

The present invention encompasses compounds of Formula I: as well as the pharmaceutically acceptable salts thereof. The compounds are S1P/Edg1 receptor agonists and thus have immunosuppressive, anti-inflammatory and hemostatic activities by modulating leukocyte trafficking, sequestering lymphocytes in secondary lymphoid tissues, and enhancing vascular integrity. The invention is also directed to pharmaceutical compositions containing such compounds and methods of treatment or prevention.

(3,4-disubstituted)propanoic carboxylates as S1P (Edg) receptor agonists

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Millburn, NJ, United States of America

Pei Huo