Download Metabolic Disorders/ Cardiovascular Disease PPAR

September2005
2006
September
Metabolic Disorders/
Cardiovascular Disease
PPAR Fact Sheet
Plexxikon’s PPAR (Peroxisome Proliferator-Activated Receptor) pan-agonist represents a significant
novel potential drug for the treatment of clinical conditions in metabolic and metabolic-related
cardiovascular disease. The company has identified novel pan-active molecules that target three
separately validated isoforms of PPAR - alpha, delta and gamma - utilizing its proprietary ScaffoldBased Drug DiscoveryTM platform. Recent studies in animals and humans have demonstrated a
clear rationale for a compound targeting these PPAR subtypes to provide a combination of
triglyceride, LDL and glucose lowering activities, coupled with increases in HDL and reverse
cholesterol transport. Biochemical and biological testing of Plexxikon compounds in vitro and in vivo
demonstrate pharmaceutically relevant characteristics in terms of potency and efficacy.
Plexxikon’s agonist compounds represent an entirely new class of orally active, anti-hyperglycemic,
lipid-modulating, insulin-sensitizing compounds that could eventually be used in the treatment of a
variety of metabolic and cardiovascular diseases, including Type II diabetes, impaired glucose
tolerance, dyslipidemia, hypertension, metabolic syndrome X, and possibly other diseases in which
PPARs have been implicated. Additionally, synergies of such a combination may enable lower
dosing and consequently mitigate side effects and toxicities observed with current therapies.
Although treatment options for Type II diabetes are available, their usefulness is significantly limited
due to their failure to ameliorate concurrent hyperglycemia and hyperlipidemia (e.g. triglycerides,
LDL-cholesterol) or to raise HDL-cholesterol, in addition to their side effects.
Impact of PPAR-Targeted Agonists on Metabolic Endpoints (Humans)
PPAR Target
PPARα
Glucose
IS
No Effect
No Effect
TG
FFA
LDL
PPARδa
Edema, weight gain, anemia, ↑ LDLNo Effect cholesterol, requirement to monitor liver
No Effect function
PPARα/PPARγ
PPARα/PPARγ/ PPARδa
(?)
No Effect
No Effect
(?)
Limitations
Ineffective on glucose and insulin
sensitivity
PPARγ
(Actos)
(Avandia)
HDL
No Effect
Less validation for PPARδ
No Effect
No Effect Edema, weight gain, anemia, ↑ LDLcholesterol, requirement to monitor liver
function
Less validation for PPARδ
Abbreviations: IS, insulin sensitivity; TG, triglycerides; FFA, free fatty acids; LDL, low-density lipoprotein
cholesterol; HDL, high-density lipoprotein
a Effects in obese, rhesus monkeys
PPAR Fact Sheet
Plexxikon’s PPAR Pan-Agonist Evolution from Scaffold to Lead
EC50
PPARγ = 470µM
PPARα = 38%@200µM
PPARδ = >>200µM
EC50
PPARα = 1.3µM
PPARδ = 9.1µM
PPARγ = 1.7µM
EC50
PPARα = 0.89µM
PPARδ = 0.99µM
PPARγ = 0.06µM
Plexxikon has characterized (in vitro and in vivo) a number of PPAR agonists based on
multiple chemical scaffolds.
IV and oral PK studies have demonstrated favorable
pharmaceutical properties including excellent oral bioavailability. In vivo studies in a number
of model systems have been completed, demonstrating good biological activity without
observable clinical toxicity. The studies have demonstrated significant reduction of
triglycerides and glucose, significant increase of HDL cholesterol and adiponectin, without
significant weight gain.
Using the Scaffold-Based Drug DiscoveryTM platform, Plexxikon has demonstrated that a
weakly active scaffold can be developed into selective, dual, or pan-active agonists, rapidly
and efficiently, with excellent pharmaceutical properties. In September 2004, Plexxikon
conducted a first-in-man study. In October 2004, Plexxikon signed a collaboration agreement
with Wyeth Pharmaceuticals to license and further develop Plexxikon’s clinical lead PPAR
pan-agonist, PLX204, which is now in Phase 2 clinical testing. The collaborators also are
developing additional PPAR compounds, now at the preclinical development stage, as
distinct products to address other metabolic disorders, such as insulin resistance,
dyslipidemia and obseity.
Plexxikon Platform Permits Selectivity & Pan Activity
PPARα
PPARγ
PPARδ
Pan Active
++
++
++
γ - Selective
+
+++
+
α- Selective
++
+
-
δ- Selective
+
+
+++
α, γ - Dual
++
++
-
α, δ - Dual
++
+
+++
γ,δ - Dual
-
+
++
+++ = < 100 nM; ++ < 1 µM; + > 1 µM; - > 200 µM
Contact:
Kathleen Sereda Glaub
Plexxikon Inc.
President
Phone: 510.647.4009
Fax: 510.548.8014
[email protected]
www.plexxikon.com