Ligand Pharmaceuticals, Inc.

Phenomix Corporation

Forest Laboratories Holdings Limited (bm)

Activx Biosciences, Inc.

David T Winn

David Alan Campbell

Juan Manuel Betancort

Lin Zhi

Todd Kevin Jones

Christopher Michael Tegley

Lawrence G Hamann

James Patrick Edwards

Sarah J West

Mark E Goldman

Luc J Farmer

Robert L Davis

Charlotte Lf Pooley

Steven K White

Chan Kou Hwang

Charlotte L F Pooley

Dipeptidyl peptidase IV (DPP-IV)-inhibiting compounds are provided that have formula I: wherein n is 1 to 3; X is CHS; O; CFor C(CH); Z is H; halogen; hydroxyl; (C)alkoxy; (C)alkyl; (C)cycloalkyl; phenyl; or heteroaryl; where the phenyl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; optionally, X together with an adjacent ring carbon and Z form a fused cyclopropyl; and optionally, one of the bonds in the ring containing X is a double bond; and CrR, R, R, R, Rand Rare as described herein. Methods for preparing these compounds, and methods for treating diabetes, especially Type II diabetes, and other related diseases are described using the compounds of formula I in pharmaceutical compositions which contain these compounds. Pharmaceutical compositions which contain combinations of these compounds with other antidiabetic agents are also described herein. 

Heterocyclic boronic acid compounds

The present invention provides compositions and methods for assessing profiles of catalytically active enzymes in compositions containing a plurality of proteins. In preferred embodiments, the enzyme is a hydrolase, most preferably a cysteine protease. The methods described herein use activity based probes ('ABPs') that have an affinity moiety for directing the binding of the ABP to one or more catalytically active target enzymes, a reactive group for forming a covalent bond at an active site of the target enzyme(s), and a TAG (e.g., a detectable label, preferably a fluorophore). One or more ABPs may be combined with a protein-containing sample under conditions for binding and reaction of the ABP(s) with target enzyme(s) that are present in the sample. The resulting products may then be used to assess the active enzyme profile of the sample, and can be correlated to the presence, amount, or activity of one or more target enzyme(s) present in the original complex protein mixture. 

Activity-based probes and methods of their preparation and use

The present invention is directed to a method of treatment of a malcondition that can be regulated or normalized via inhibition of DPP-IV. The method involves administration of an effective amount of a pyrrolidine compound of the invention, such as would be present in a pharmaceutical composition of the invention, to mammals, especially humans, to affect a malcondition that can be regulated or normalized via inhibition of DPP-IV.

Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV

The present invention is directed to pyrrolidinylaminoacetyl pyrrolidine boronic acid compounds that display selective, potent dipeptidyl peptidase IV inhibitory activity. These compounds are useful for the treatment of disorders that can be regulated or normalized via inhibition of DPP-IV including those characterized by impaired glycemic control such as Diabetes Mellitus and related conditions. The compounds can be administered alone or with another medicament that displays pharmacological activity for treatment of these and other diseases.

Compounds that selectively inhibit dipeptidyl peptidase-IV over closely related dipeptidyl peptidases are those of Formula (I): as well as pharmaceutically acceptable salts thereof, cyclic isomers thereof, prodrugs thereof, and solvates thereof, where all the variables are defined herein. These compounds can be used, alone or in combination with other drugs, for the treatment of diabetes and related diseases.

Compounds and methods for selective inhibition of dipeptidyl peptidase-IV

Certain constrained cyano compounds are useful as inhibitors of post-proline/alanine cleaving amino-dipeptidases. Accordingly, these compounds can be employed, alone or with another therapeutic agent, to treat diabetes (especially, Type II diabetes), hyperglycemia, Syndrome X, diabetic complications, hyperinsulinemia, obesity, atherosclerosis and related diseases, as well as various immunomodulatory diseases and chronic inflammatory bowel disease.

Constrained cyano compounds

In the context of synthesizing heterocyclic boronic acid compounds, a convergent synthetic methodology is particularly efficient for preparing boropyrrolidines and derivatives of boropyrrolidines.

Methods of preparing heterocyclic boronic acids and derivatives thereof

Methyl and ethyl substituted pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV

Dipeptidyl peptidase IV (DPP-IV)-inhibiting compounds are provided that have formula I: wherein n is 1 to 3; X is CH; S; O; CFor C(CH); Z is H; halogen; hydroxyl; (C)alkoxy; (C)alkyl; (C)cycloalkyl; phenyl; or heteroaryl; where the phenyl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; optionally, X together with an adjacent ring carbon and Z form a fused cyclopropyl; and optionally, one of the bonds in the ring containing X is a double bond; and CrR, R, R, R, Rand Rare as described herein. Methods for preparing these compounds, and methods for treating diabetes, especially Type II diabetes, and other related diseases are described using the compounds of formula I in pharmaceutical compositions which contain these compounds. Pharmaceutical compositions which contain combinations of these compounds with other antidiabetic agents are also described herein. 

The present invention is directed to pyrrolidinylaminoacetyl pyrrolidine boronic acid compounds that display selective, potent dipeptidyl peptidase IV (DPP-IV) inhibitory activity. These compounds are useful for the treatment of disorders that can be regulated or normalized via inhibition of DPP-IV including those characterized by impaired glycemic control such as Diabetes Mellitus and related conditions. The compounds can be administered alone or with another medicament that displays pharmacological activity for treatment of these and other diseases.

Non-steroidal compounds which are high affinity, high selectivity modulators for steroid receptors are disclosed. Also disclosed are pharmaceutical compositions incorporating such compounds, methods for employing the disclosed compounds and compositions for treating patients requiring steroid receptor agonist or antagonist therapy, intermediates useful in the preparation of the compounds and processes for the preparation of the steroid receptor modulator compounds.

Steroid receptor modulator compounds and methods

Intermediates for preparation of steroid receptor modulator compounds

Process for preparing steroid receptor modulator compounds

Methods for stereospecific synthesis of 9-cis olefins and retinoids. In one particular aspect, a cis olefin is generated via a lactol ring opening with complete retention of double bond configuration.

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San Diego, CA, United States of America

David T Winn