The cloning of the mouse PPAR alpha
gene in 1990 by Issemann and Green [1] stimulated intense interest in this
family of nuclear receptors, and research efforts over the next decade established
important roles for the PPAR isotypes in glucose and lipoprotein metabolism,
inflammation, and atherosclerosis. Though the fibrates (PPAR-α agonists) had
been used for the treatment of dyslipidemia for nearly 40 years, the discovery
of the insulin-sensitizing effects of PPAR-γ agonists brought about the development and
commercialization of the thiazolidinedione (TZD) class of oral anti-hyperglycemic
medications: troglitazone, approved by the FDA in 1997, and pioglitazone and
rosiglitazone, both approved by the FDA in 1999. The withdrawal of troglitazone
from the market in 2000 was an early indicator of the potential safety issues
of PPAR drugs. Even so, the clinical use of fibrates and TZDs has allowed for a
better understanding of the safety profiles and safety issues of PPAR-α and
PPAR-γ
agonists [2, 3].
At the beginning of this decade,
many pharmaceutical companies had development programs focused on delivering
“new and improved” PPAR agonists to the market.
For example, several programs were developing PPAR-α/γ dual agonists (i.e., glitazars) for the
treatment of type 2 diabetes. Although
preliminary data from various PPAR-α/γ
dual agonist research programs was promising, nearly all of these research
programs were discontinued due to safety issues identified during clinical
testing and/or during preclinical testing [4–6]. More recently, the highly publicized (and
controversial) meta-analysis of rosiglitazone reported by Nissen and Wolski [7]
called into question the safety of the TZDs and prompted changes to the labels of
both rosiglitazone and pioglitazone.
And yet, the
promise of the therapeutic potential of PPAR drugs remains. A PubMed search
using the term “peroxisome proliferator-activated receptor” yielded 1578
manuscripts (161 of which were review articles) between January 1 and December 1,
2008. In addition to the roles of the
PPAR isotypes in lipid/lipoprotein/glucose metabolism, additional roles in
diverse physiological processes and disease states are currently being investigated. As additional functions are identified; the
PPARs will continue to be important molecular targets for identifying ligands
(drugs) with potential applications to reproduction and fertility, normal
development; function of the reproductive, gastrointestinal, respiratory,
and central nervous systems; skin biology and wound healing; and cell cycle
control and cancer.
Reports highlighting both
challenges and opportunities in PPAR drug development are included in this
special issue. For example, edema,
weight gain, and a reduction in bone mass (particularly in women) are
challenges limiting the clinical utility of the currently marketed TZDs. The
renal and vascular mechanisms of TZD-induced fluid retention are reviewed by
Yang and Soodvilai, and the recent clinical data describing the effects of TZDs
on bone are reviewed by Schwartz. In
contrast, several reports highlight opportunities in PPAR drug development. Deeg
and Tan compare the effects of rosiglitazone and pioglitazone on lipids,
lipoproteins, and apolipoproteins as reported in head-to-head, randomized
clinical studies. Two papers describe the effects of PPARs/PPAR ligands on immune/inflammatory
responses; Fernandez reviews the roles of the PPARs in modulating the
immune/inflammatory response in atherosclerosis, while Yamashita reviews the
receptor-independent effects of PPAR-α and PPAR-γ ligands on cysteinyl leukotriene production in
mast cells as it relates to the development of potential anti-asthma
medications. Technological and
methodological approaches that may prove useful in the identification and
assessment of new PPAR drugs are also reported. Clarke et al. describe
an approach used to determine the species differences in plasma protein binding
to MBX-102, a novel PPAR-γ
agonist currently in Phase 2 clinical development, and the corresponding
differences in PPAR-γ
activation across species. Cho et al. review the role of PPARs in
metabolic disorders as well as various strategies and technologies used in the
identification and assessment of PPAR drugs. Finally, Miyachi and Hashimoto
describe the synthesis and SAR of subtype-specific PPAR agonists derived from a
single 3,4-disubstituted phenylpropanoic acid
“versatile template” scaffold, and Higgins and Mantzoros review the
development and safety profile of INT-131, a potent non-TZD selective PPAR
modulator (SPPARM) currently in Phase 2 clinical development.
In conclusion, though the full
therapeutic potential of PPARs has yet to be realized, and serious safety
issues are associated with the currently marketed PPAR drugs (PPAR-α and PPAR-γ),
there remains intense interest in exploring new physiological roles of the
PPARs and in the identification of new and improved PPAR agonists drugs.
Jane A. PinaireAnne Reifel MillerFrancine M. Gregoire
IssemannI.GreenS.Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators1990347629464565010.1038/347645a0RubenstrunkA.HanfR.HumD. W.FruchartJ.-C.StaelsB.Bart.Staels@pasteur-lille.frSafety issues and prospects for future generations of PPAR modulators2007177181065108110.1016/j.bbalip.2007.02.003ShearerB. G.barry.g.shearer@GSK.comBillinA. N.andrew.n.billin@GSK.comThe next generation of PPAR drugs: do we have the tools to find them?2007177181082109310.1016/j.bbalip.2007.05.005FiévetC.FruchartJ.-C.StaelsB.bart.staels@pasteur-lille.frPPARα and PPARγ dual agonists for the treatment of type 2 diabetes and the metabolic syndrome20066660661410.1016/j.coph.2006.06.009WaitesC. R.DominickM. A.SandersonT. P.SchillingB. E.beth.schilling@bms.comNonclinical safety evaluation of muraglitazar, a novel PPARα/γ agonist2007100124825810.1093/toxsci/kfm193BalakumarP.pbala2006@gmail.comRoseM.GantiS. S.KrishanP.SinghM.PPAR dual agonists: are they opening Pandora's Box?2007562919810.1016/j.phrs.2007.03.002NissenS. E.nissens@ccf.orgWolskiK.Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes2007356242457247110.1056/NEJMoa072761