T2384, a Novel Antidiabetic Agent with Unique Peroxisome Proliferator-activated Receptor γ Binding Properties

Abstract

The nuclear hormone receptor peroxisome proliferator-activated receptor γ (PPARγ) plays central roles in adipogenesis and glucose homeostasis and is the molecular target for the thiazolidinedione (TZD) class of antidiabetic drugs. Activation of PPARγ by TZDs improves insulin sensitivity; however, this is accompanied by the induction of several undesirable side effects. We have identified a novel synthetic PPARγ ligand, T2384, to explore the biological activities associated with occupying different regions of the receptor ligand-binding have and with the ligand-binding of PPARγ The different by of with PPARγ in and receptor in We and activities for the novel in in with to insulin in the of and of with with to the side by glucose with the and regions of the receptor ligand-binding a of biological to the of insulin associated with of the We a for a novel class of PPARγ of for of The nuclear hormone receptor peroxisome proliferator-activated receptor γ (PPARγ) plays central roles in adipogenesis and glucose homeostasis and is the molecular target for the thiazolidinedione (TZD) class of antidiabetic drugs. Activation of PPARγ by TZDs improves insulin sensitivity; however, this is accompanied by the induction of several undesirable side effects. We have identified a novel synthetic PPARγ ligand, T2384, to explore the biological activities associated with occupying different regions of the receptor ligand-binding have and with the ligand-binding of PPARγ The different by of with PPARγ in and receptor in We and activities for the novel in in with to insulin in the of and of with with to the side by glucose with the and regions of the receptor ligand-binding a of biological to the of insulin associated with of the We a for a novel class of PPARγ of for of proliferator-activated receptor γ proliferator-activated receptor proliferator-activated receptor is a of the nuclear hormone receptor of with and a of of and glucose homeostasis PPARγ and different of the is in is in of and of have PPARγ a of and a with the in The roles PPARγ plays in and have and the PPARγ and the of PPARγ the target for the thiazolidinedione class of antidiabetic and have in with insulin to in TZDs glucose and and in in and in in the undesirable side associated with and side of the PPARγ with the of PPARγ in in insulin have identified in PPARγ associated with to of with a in the of and with a in The in of this the a of PPARγ a of and the of PPARγ in and insulin The in associated with insulin and of and and a of the in of and in in to the of PPARγ the side associated with the insulin a PPARγ receptor and the with a PPARγ the side associated with of the receptor the PPARγ ligand-binding is a with a of in the in this in a with central and the the to a with the of the side is for the in a with this the for receptor with and to different regions of this and of receptor a and PPARγ ligand, T2384, this class of a of and to PPARγ in with biological activities in the in of the have for this in of glucose and insulin the induction of and and ligand-binding and for the a with of in in and in for with the for The in and The the by a of of the to the a of the in the of to and the the of and to by the in of the PPARγ in the The of the with PPARγ a with and in with in by in The by a and of and by a of the of PPARγ and the and by a of to the The PPARγ to in and with of The to for The of PPARγ and to with of and of a the of The to for of PPARγ with by with of the and of the and of PPARγ with with the of in the of and the in The a of and in and and the The The PPARγ in with a The in with of a of PPARγ with by molecular PPARγ a The of for the PPARγ and of for the in and with and in The and in the for the to the the in the ligand-binding and the of and is the The in for the and the and a of the and the of in a PPARγ of for and a of and the The and of in and to and to for of to in of the and and and for glucose and for and for PPARγ and is the thiazolidinedione class of PPARγ to the receptor with to of with a of and PPARγ a for in for receptor in with the PPARγ to the with a the of the to by by in this the receptor with of PPARγ in the of for a have a receptor with a the of a to the of a of and the of and to in of with in to by in in to the of to the with in the in the of of to PPARγ the receptor and of and the and the to of target PPARγ and receptor and a a of of in a and a PPARγ and a a and is a the The the is the is and the is to the for is is with different to the ligand-binding of We different of and with the receptor for the different activities in and in of and in with and of and in with and in for of PPARγ We the of with the PPARγ ligand-binding to a of the with in a different and of PPARγ in the ligand-binding with in a with and in a this the the and and with in and of the of T2384, the is of and of The and the a the and this is the The and PPARγ the and the receptor and the the TZDs with the of the in the is a of the of this of the receptor and the activities of in of PPARγ ligand-binding in with of the PPARγ in a in in the of in a The is for for for for for and for of PPARγ The ligand-binding is in a and is in a of the ligand-binding of of the PPARγ with in a The is the in and the a for the of the ligand-binding of the of the PPARγ with The is the in and the a for the The the and the with with in of the PPARγ the of to the ligand-binding The in in and in a with the with to the of the and the a of the a novel by and the We this the and the by the the in the in the with the in in and is in the the is associated with and to of and and the with the and the the of T2384, and and to PPARγ in different in in this in different regions of the ligand-binding to the of to the to the of this PPARγ and and of in and the ligand-binding of in the and and to the of the and the The PPARγ a the the and in this the the of the by the of and the for of the and of for the receptor and the and the of in to is in the receptor the of the associated with of in with the in a of the of to the and the to PPARγ in the the a novel in the ligand-binding of PPARγ by with in of to for of to PPARγ in the of the by to PPARγ in and the of the of the receptor the of the by to PPARγ in and the of the in the for of receptor The in and is the for the and and the of for the with this the of in the the to the the the of by is T2384, to T2384, the to the receptor in the the and the associated with of the of the and of receptor in the PPARγ in to different biological and and the and by in different regions in the PPARγ ligand-binding the in of in the to the of molecular in the for the for The by the of with the the glucose and insulin in insulin insulin with with of of insulin and glucose in a and and of and and the in insulin with improves glucose and insulin in and of and in insulin in and the the side by different in this in in the a in the the of the with the and in the in the with of the of by by and the side of the and by and with insulin and side a of the of target The of to of is by with and the of of of ligand, receptor is and and in the of a is the of the of target several the receptor to have the ligand-binding of PPARγ a is the with of nuclear in a the occupying of the the thiazolidinedione of and the of PPARγ the receptor in to of the PPARγ ligand-binding to in and of a of different of PPARγ with different of different have to with the PPARγ ligand-binding the molecular in the in with the to to the receptor in a a by the of is a biological this different for the nuclear receptor different biological this of the of a PPARγ ligand, T2384, to explore the biological and of different regions of the of of a the PPARγ and to the receptor in different have the and the a to for the of the in in to in a of the thiazolidinedione and the to the of the the and the receptor to in and with in the of the in the the of the this a of the PPARγ ligand-binding and with a with to the and biological of to the receptor in this novel to have PPARγ in of receptor the of a a of of ligand, a of PPARγ in and PPARγ the of the and of the the of is and is by the of and of the for the receptor is to of and PPARγ in a for of this by the different with to the and of the PPARγ in the this the the of of the of the this molecular in the ligand-binding of the and to in the in the of the of the the of the a PPARγ in the of the in the and the of the to PPARγ the the of with PPARγ in and by the of of receptor of with PPARγ and have the to the receptor and different in different in a novel and in in the glucose and insulin in a and the of to with and and in the a in the the however, of with the and with and in this with to the receptor the a novel class of PPARγ insulin the side of and a is to of the PPARγ to of of to for and insulin to PPARγ and in the the insulin and the undesirable side by PPARγ receptor in insulin undesirable in the and the of to this receptor a in side and in insulin in with of the receptor and and in PPARγ in to T2384, to have this of receptor for and have to insulin in is to of to PPARγ and in the of and have of the the in the of with a of and and the PPARγ in the in of insulin the undesirable side effects. The of the the of a to novel PPARγ the of proliferator-activated receptor γ proliferator-activated receptor proliferator-activated receptor is a of the nuclear hormone receptor of with and a of of and glucose homeostasis PPARγ and different of the is in is in of and of have PPARγ a of and a with the in The roles PPARγ plays in and have and peroxisome proliferator-activated receptor thiazolidinedione ligand-binding receptor nuclear receptor peroxisome proliferator-activated receptor thiazolidinedione ligand-binding receptor nuclear receptor The the PPARγ and the of PPARγ the target for the thiazolidinedione class of antidiabetic and have in with insulin to in TZDs glucose and and in in and in in the undesirable side associated with and side of the PPARγ with the of PPARγ in in insulin have identified in PPARγ associated with to of with a in the of and with a in The in of this the a of PPARγ a of and the of PPARγ in and insulin The in associated with insulin and of and and a of the in of and in in to the of PPARγ the side associated with the insulin a PPARγ receptor and the with a PPARγ the side associated with of the receptor the The PPARγ ligand-binding is a with a of in the in this in a with central and the the to a with the of the side is for the in a with this the for receptor with and to different regions of this and of receptor a and PPARγ ligand, T2384, this class of a of and to PPARγ in with biological activities in the in of the have for this in of glucose and insulin the induction of and and ligand-binding and for the a with of in in and in for with the for The in and The the by a of of the to the a of the in the of to and the the of and to by the in of the PPARγ in the The of the with PPARγ a with and in with in by in The by a and of and by a of the of PPARγ and the and by a of to the The PPARγ to in and with of The to for The of PPARγ and to with of and of a the of The to for of PPARγ with by with of the and of the and of PPARγ with with the of in the of and the in The a of and in and and the The The PPARγ in with a The in with of a of PPARγ with by molecular PPARγ a The of for the PPARγ and of for the in and with and in The and in the for the to the the in the ligand-binding and the of and is the The in for the and the and a of the and the of in a PPARγ of for and a of and the The and of in and to and to for of to in of the and and and for glucose and for and for and ligand-binding and for the a with of in in and in for with the for The in and The the by a of of the to the a of the in the of to and the the of and to by the in of the PPARγ in the The of the with PPARγ a with and in with in by in The by a and of and by a of the of PPARγ and the and by a of to the The PPARγ to in and with of The to for The of PPARγ and to with of and of a the of The to for of PPARγ with by with of the and of the and of PPARγ with with the of in the of and the in The a of and in and and the The The PPARγ in with a The in with of a The of PPARγ with by molecular PPARγ a The of for the PPARγ and of for the in and with and in The and in the for the to the the in the ligand-binding and the PPARγ of for and a of and the The and of in and to and to for of to in of the and and and for glucose and for and for PPARγ and is the thiazolidinedione class of PPARγ to the receptor with to of with a of and PPARγ a for in for receptor in with the PPARγ to the with a the of the to by by in this the receptor with of PPARγ in the of for a have a receptor with a the of a to the of a of and the of and to in of with in to by in in to the of to the with in the in the of of to PPARγ the receptor and of and the and the to of target PPARγ and receptor and a a of of in a and a PPARγ and a a and is a the The the is the is and the is to the for is is with different to the ligand-binding of We different of and with the receptor for the different activities for of PPARγ We the of with the PPARγ ligand-binding to a of the with in a different and of PPARγ in the ligand-binding with in a with and in a this the the and and with in and of the of T2384, the is of and of The and the a the and this is the The and PPARγ the and the receptor and the the TZDs with the of the in the is a of the of this of the receptor and the activities of in of PPARγ ligand-binding in with of the PPARγ in a in in the of in a The is for for for for for and for of PPARγ The ligand-binding is in a and is in a of the ligand-binding of of the PPARγ with in a The is the in and the a for the of the ligand-binding of the of the PPARγ with The is the in and the a for the The the and the with with in of the PPARγ the of to the ligand-binding The in in and in a with the with to the of the and the a of the a novel by and the We this the and the by the the in the in the with the in in and is in the the is associated with and to of and and the with the and the the of T2384, and and to PPARγ in different in in this in different regions of the ligand-binding to the of to the to the of this PPARγ and and of in and the ligand-binding of in the and and to the of the and the The PPARγ a the the and in this the the of the by the of and the for of the and of for the receptor and the and the of in to is in the receptor the of the associated with of in with the in a of the of to the and the to PPARγ in the the a novel in the ligand-binding of PPARγ by with in of to for of to PPARγ in the of the by to PPARγ in and the of the of the receptor the of the by to PPARγ in and the of the in the for of receptor The in and is the for the and and the of for the with this the of in the the to the the the of by is T2384, to T2384, the to the receptor in the the and the associated with of the of the and of receptor in the PPARγ in to different biological and and the and by in different regions in the PPARγ ligand-binding the in of in the to the of molecular in the for the for The by the of with the the glucose and insulin in insulin insulin with with of of insulin and glucose in a and and of and and the in insulin with improves glucose and insulin in and of and in insulin in and the the side by different in this in in the a in the the of the with the and in the in the with of the of by by and the side of the and by and with insulin and side PPARγ and is the thiazolidinedione class of PPARγ to the receptor with to of with a of and PPARγ a for in for receptor in with the PPARγ to the with a the of the to by by in this the receptor with of PPARγ in the of for a have a receptor with a the of a PPARγ to the of a of and the of and to in of with in to by in in to the of to the with in the in the of of to PPARγ the receptor and of and the and the to of target PPARγ and receptor and a a of of in a and a PPARγ and a a and is a the The the is the is and the is to the for is is with different to the ligand-binding of We different of and with the receptor for the different activities for of PPARγ We the of with the PPARγ ligand-binding to a of the with in a different and of PPARγ in the ligand-binding with in a with and in a this the the and and with in and of the of T2384, the is of and of The and the a the and this is the The and PPARγ the and the receptor and the the TZDs with the of the in the is a of the of this of the receptor and the activities of in The of the PPARγ the of to the ligand-binding The in in and in a with the with to the of the and the a of the a novel by and the We this the and the by the the in the in the with the in in and is in the the is associated with and to of and and the with the and the the of T2384, and and to PPARγ in different in in this in different regions of the ligand-binding to the of to the to the of this PPARγ and and of in and the ligand-binding of The in the and and to the of the and the The PPARγ a the the and in this the the of the by the The of and the for of the and of for the receptor and the and the of in to is in the receptor the of the associated with of in with the in a of the of to the and the to PPARγ in the the a novel in the ligand-binding of PPARγ by with in of The for the with this the of in the the to the the the of by is T2384, to T2384, the to the receptor in the the and the associated with of the of the and of receptor in the PPARγ in to different biological and and the and by in different regions in the PPARγ ligand-binding the in of in the to the of molecular in the for the for The by the of with the the glucose and insulin in insulin insulin with with of of insulin and glucose in a and and of and and the in insulin with the side by different in this in in the a in the the of the with the and in the in the with of the of by by and the side of the and by and with insulin and side a of the of target The of to of is by with and the of of of ligand, receptor is and and in the of a is the of the of target several the receptor to have the ligand-binding of PPARγ a is the with of nuclear in a the occupying of the the thiazolidinedione of and the of PPARγ the receptor in to of the PPARγ ligand-binding to in and of a of different of PPARγ with different of different have to with the PPARγ ligand-binding the molecular in the in with the to to the receptor in a a by the of is a biological this different for the nuclear receptor different biological this of the of a PPARγ ligand, T2384, to explore the biological and of different regions of the of of a the PPARγ and to the receptor in different have the and the a to for the of the in in to in a of the thiazolidinedione and the to the of the the and the receptor to in and with in the of the in the the of the this a of the PPARγ ligand-binding and with a with to the and biological of to the receptor in this novel to have PPARγ in of receptor the of a a of of ligand, a of PPARγ in and PPARγ the of the and of the the of is and is by the of and of the for the receptor is to of and PPARγ in a for of this by the different with to the and of the PPARγ in the this the the of of the of the this molecular in the ligand-binding of the and to in the in the of the of the the of the a PPARγ in the of the in the and the of the to PPARγ the the of with PPARγ in and by the of of receptor of with PPARγ and have the to the receptor and different in different in a novel and in in the glucose and insulin in a and the of to with and and in the a in the the however, of with the and with and in this with to the receptor the a novel class of PPARγ insulin the side of and a is to of the PPARγ to of of to for and insulin to PPARγ and in the the insulin and the undesirable side by PPARγ receptor in insulin undesirable in the and the of to this receptor a in side and in insulin in with of the receptor and and in PPARγ in to T2384, to have this of receptor for and have to insulin in is to of to PPARγ and in the of and have of the the in the of with a of and and the PPARγ in the in of insulin the undesirable side effects. The of the the of a to novel PPARγ the of a of the of target The of to of is by with and the of of of ligand, receptor is and and in the of a is the of the of target PPARγ several the receptor to have the ligand-binding of PPARγ a is the with of nuclear in a the occupying of the the thiazolidinedione of and the of PPARγ the receptor in to of the PPARγ ligand-binding to in and of a of different of PPARγ with different of different have to with the PPARγ ligand-binding the molecular in the in with the to to the receptor in a a by the of is a biological this different for the nuclear receptor different biological this of the of a PPARγ ligand, T2384, to explore the biological and of different regions of the of of a the PPARγ and to the receptor in different have the and the a to for the of the in in to in a of the thiazolidinedione and the to the of the the and the receptor to in and with in the of the in the the of the this a of the PPARγ ligand-binding and with a with to the and biological of to the receptor in this novel to have PPARγ in of receptor the of a a of of ligand, a of PPARγ in and PPARγ the of the and of the the of is and is by the of and of the for the receptor is to of and PPARγ in a for of We this by the different with to the and of the PPARγ in the this the the of of the of the this molecular in the ligand-binding of the and to in the in the of the of the the of the a PPARγ in the of the in the and the of the to PPARγ the the of with PPARγ in and by the of of receptor of with PPARγ and have the to the receptor and different in different in a novel and in in the glucose and insulin in a and the of to with and and in the a in the the however, of with the and with and in this with to the receptor the a novel class of PPARγ insulin the side of and a is to of the PPARγ to of of to for and insulin to PPARγ and in the the insulin and the undesirable side by PPARγ receptor in insulin undesirable in the and the of to this receptor a in side and in insulin in with of the receptor and and in PPARγ in to T2384, to have this of receptor for and have to insulin in is to of to PPARγ and in the of and have of the the in the of with a of and and the PPARγ in the in of insulin the undesirable side effects. The of the the of a to novel PPARγ the of We and for and of We and for and of the