char = R;code = 82
char = a;code = 97
char = t;code = 116
char = ;code = 32
char = U;code = 85
char = r;code = 114
char = i;code = 105
char = n;code = 110
char = a;code = 97
char = r;code = 114
char = y;code = 121
char = ;code = 32
char = B;code = 66
char = l;code = 108
char = a;code = 97
char = d;code = 100
char = d;code = 100
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = C;code = 67
char = a;code = 97
char = r;code = 114
char = c;code = 99
char = i;code = 105
char = n;code = 110
char = o;code = 111
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = e;code = 101
char = s;code = 115
char = i;code = 105
char = s;code = 115
char = ;code = 32
char = b;code = 98
char = y;code = 121
char = ;code = 32
char = D;code = 68
char = u;code = 117
char = a;code = 97
char = l;code = 108
char = -;code = 45
char = A;code = 65
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = P;code = 80
char = P;code = 80
char = A;code = 65
char = R;code = 82
char = a;code = 97
char = l;code = 108
char = p;code = 112
char = h;code = 104
char = a;code = 97
char = ;code = 32
char = +;code = 43
char = ;code = 32
char = g;code = 103
char = a;code = 97
char = m;code = 109
char = m;code = 109
char = a;code = 97
char = ;code = 32
char = A;code = 65
char = g;code = 103
char = o;code = 111
char = n;code = 110
char = i;code = 105
char = s;code = 115
char = t;code = 116
char = s;code = 115
char = .;code = 46
result sql = Rat Urinary Bladder Carcinogenesis by Dual-Acting PPARalpha + gamma Agonists.
Rat Urinary Bladder Carcinogenesis by Dual-Acting PPARalpha + gamma Agonists.
char = D;code = 68
char = e;code = 101
char = s;code = 115
char = p;code = 112
char = i;code = 105
char = t;code = 116
char = e;code = 101
char = ;code = 32
char = c;code = 99
char = l;code = 108
char = i;code = 105
char = n;code = 110
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = m;code = 109
char = i;code = 105
char = s;code = 115
char = e;code = 101
char = ,;code = 44
char = ;code = 32
char = d;code = 100
char = u;code = 117
char = a;code = 97
char = l;code = 108
char = -;code = 45
char = a;code = 97
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = a;code = 97
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = a;code = 97
char = t;code = 116
char = o;code = 111
char = r;code = 114
char = s;code = 115
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = P;code = 80
char = P;code = 80
char = A;code = 65
char = R;code = 82
char = a;code = 97
char = l;code = 108
char = p;code = 112
char = h;code = 104
char = a;code = 97
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = g;code = 103
char = a;code = 97
char = m;code = 109
char = m;code = 109
char = a;code = 97
char = ;code = 32
char = (;code = 40
char = h;code = 104
char = e;code = 101
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = m;code = 109
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = P;code = 80
char = P;code = 80
char = A;code = 65
char = R;code = 82
char = a;code = 97
char = l;code = 108
char = p;code = 112
char = h;code = 104
char = a;code = 97
char = +;code = 43
char = g;code = 103
char = a;code = 97
char = m;code = 109
char = m;code = 109
char = a;code = 97
char = ;code = 32
char = a;code = 97
char = g;code = 103
char = o;code = 111
char = n;code = 110
char = i;code = 105
char = s;code = 115
char = t;code = 116
char = s;code = 115
char = );code = 41
char = ;code = 32
char = h;code = 104
char = a;code = 97
char = v;code = 118
char = e;code = 101
char = ;code = 32
char = e;code = 101
char = x;code = 120
char = p;code = 112
char = e;code = 101
char = r;code = 114
char = i;code = 105
char = e;code = 101
char = n;code = 110
char = c;code = 99
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = h;code = 104
char = i;code = 105
char = g;code = 103
char = h;code = 104
char = ;code = 32
char = a;code = 97
char = t;code = 116
char = t;code = 116
char = r;code = 114
char = i;code = 105
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = r;code = 114
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = e;code = 101
char = c;code = 99
char = l;code = 108
char = i;code = 105
char = n;code = 110
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = e;code = 101
char = a;code = 97
char = r;code = 114
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = c;code = 99
char = l;code = 108
char = i;code = 105
char = n;code = 110
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = d;code = 100
char = e;code = 101
char = v;code = 118
char = e;code = 101
char = l;code = 108
char = o;code = 111
char = p;code = 112
char = m;code = 109
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = ,;code = 44
char = ;code = 32
char = d;code = 100
char = u;code = 117
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = x;code = 120
char = i;code = 105
char = c;code = 99
char = i;code = 105
char = t;code = 116
char = y;code = 121
char = .;code = 46
char = ;code = 32
char = I;code = 73
char = n;code = 110
char = ;code = 32
char = s;code = 115
char = o;code = 111
char = m;code = 109
char = e;code = 101
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = s;code = 115
char = e;code = 101
char = s;code = 115
char = ,;code = 44
char = ;code = 32
char = d;code = 100
char = i;code = 105
char = s;code = 115
char = c;code = 99
char = o;code = 111
char = n;code = 110
char = t;code = 116
char = i;code = 105
char = n;code = 110
char = u;code = 117
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = w;code = 119
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = d;code = 100
char = u;code = 117
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = r;code = 114
char = c;code = 99
char = i;code = 105
char = n;code = 110
char = o;code = 111
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = e;code = 101
char = f;code = 102
char = f;code = 102
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = r;code = 114
char = a;code = 97
char = t;code = 116
char = ;code = 32
char = u;code = 117
char = r;code = 114
char = o;code = 111
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = l;code = 108
char = i;code = 105
char = u;code = 117
char = m;code = 109
char = ,;code = 44
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = e;code = 101
char = p;code = 112
char = i;code = 105
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = l;code = 108
char = i;code = 105
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = l;code = 108
char = a;code = 97
char = y;code = 121
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = l;code = 108
char = i;code = 105
char = n;code = 110
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = u;code = 117
char = r;code = 114
char = i;code = 105
char = n;code = 110
char = a;code = 97
char = r;code = 114
char = y;code = 121
char = ;code = 32
char = b;code = 98
char = l;code = 108
char = a;code = 97
char = d;code = 100
char = d;code = 100
char = e;code = 101
char = r;code = 114
char = ,;code = 44
char = ;code = 32
char = u;code = 117
char = r;code = 114
char = e;code = 101
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = s;code = 115
char = ,;code = 44
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = k;code = 107
char = i;code = 105
char = d;code = 100
char = n;code = 110
char = e;code = 101
char = y;code = 121
char = ;code = 32
char = p;code = 112
char = e;code = 101
char = l;code = 108
char = v;code = 118
char = i;code = 105
char = s;code = 115
char = .;code = 46
char = ;code = 32
char = C;code = 67
char = h;code = 104
char = r;code = 114
char = o;code = 111
char = n;code = 110
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = p;code = 112
char = h;code = 104
char = a;code = 97
char = r;code = 114
char = m;code = 109
char = a;code = 97
char = c;code = 99
char = o;code = 111
char = l;code = 108
char = o;code = 111
char = g;code = 103
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = a;code = 97
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = P;code = 80
char = P;code = 80
char = A;code = 65
char = R;code = 82
char = a;code = 97
char = l;code = 108
char = p;code = 112
char = h;code = 104
char = a;code = 97
char = ;code = 32
char = i;code = 105
char = s;code = 115
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = v;code = 118
char = a;code = 97
char = r;code = 114
char = i;code = 105
char = a;code = 97
char = b;code = 98
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = a;code = 97
char = s;code = 115
char = s;code = 115
char = o;code = 111
char = c;code = 99
char = i;code = 105
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = w;code = 119
char = i;code = 105
char = t;code = 116
char = h;code = 104
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = n;code = 110
char = c;code = 99
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = r;code = 114
char = a;code = 97
char = t;code = 116
char = s;code = 115
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = m;code = 109
char = i;code = 105
char = c;code = 99
char = e;code = 101
char = .;code = 46
char = ;code = 32
char = C;code = 67
char = h;code = 104
char = r;code = 114
char = o;code = 111
char = n;code = 110
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = p;code = 112
char = h;code = 104
char = a;code = 97
char = r;code = 114
char = m;code = 109
char = a;code = 97
char = c;code = 99
char = o;code = 111
char = l;code = 108
char = o;code = 111
char = g;code = 103
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = a;code = 97
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = P;code = 80
char = P;code = 80
char = A;code = 65
char = R;code = 82
char = g;code = 103
char = a;code = 97
char = m;code = 109
char = m;code = 109
char = a;code = 97
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = s;code = 115
char = o;code = 111
char = m;code = 109
char = e;code = 101
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = s;code = 115
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = a;code = 97
char = l;code = 108
char = s;code = 115
char = o;code = 111
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = u;code = 117
char = s;code = 115
char = e;code = 101
char = ;code = 32
char = c;code = 99
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char = n;code = 110
char = c;code = 99
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = r;code = 114
char = a;code = 97
char = t;code = 116
char = s;code = 115
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = m;code = 109
char = i;code = 105
char = c;code = 99
char = e;code = 101
char = .;code = 46
char = ;code = 32
char = U;code = 85
char = r;code = 114
char = o;code = 111
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = l;code = 108
char = i;code = 105
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = c;code = 99
char = e;code = 101
char = l;code = 108
char = l;code = 108
char = s;code = 115
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char = c;code = 99
char = o;code = 111
char = e;code = 101
char = x;code = 120
char = p;code = 112
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = s;code = 115
char = ;code = 32
char = P;code = 80
char = P;code = 80
char = A;code = 65
char = R;code = 82
char = a;code = 97
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char = p;code = 112
char = h;code = 104
char = a;code = 97
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char = a;code = 97
char = s;code = 115
char = ;code = 32
char = w;code = 119
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char = l;code = 108
char = l;code = 108
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char = a;code = 97
char = s;code = 115
char = ;code = 32
char = P;code = 80
char = P;code = 80
char = A;code = 65
char = R;code = 82
char = g;code = 103
char = a;code = 97
char = m;code = 109
char = m;code = 109
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char = ;code = 32
char = m;code = 109
char = a;code = 97
char = k;code = 107
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char = n;code = 110
char = g;code = 103
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char = i;code = 105
char = t;code = 116
char = ;code = 32
char = p;code = 112
char = l;code = 108
char = a;code = 97
char = u;code = 117
char = s;code = 115
char = i;code = 105
char = b;code = 98
char = l;code = 108
char = e;code = 101
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char = t;code = 116
char = h;code = 104
char = a;code = 97
char = t;code = 116
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = u;code = 117
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char = o;code = 111
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char = e;code = 101
char = l;code = 108
char = i;code = 105
char = a;code = 97
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char = ;code = 32
char = c;code = 99
char = a;code = 97
char = r;code = 114
char = c;code = 99
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char = o;code = 111
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = i;code = 105
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char = t;code = 116
char = y;code = 121
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char = o;code = 111
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char = ;code = 32
char = P;code = 80
char = P;code = 80
char = A;code = 65
char = R;code = 82
char = a;code = 97
char = l;code = 108
char = p;code = 112
char = h;code = 104
char = a;code = 97
char = +;code = 43
char = g;code = 103
char = a;code = 97
char = m;code = 109
char = m;code = 109
char = a;code = 97
char = ;code = 32
char = a;code = 97
char = g;code = 103
char = o;code = 111
char = n;code = 110
char = i;code = 105
char = s;code = 115
char = t;code = 116
char = s;code = 115
char = ;code = 32
char = m;code = 109
char = a;code = 97
char = y;code = 121
char = ;code = 32
char = b;code = 98
char = e;code = 101
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char = c;code = 99
char = a;code = 97
char = u;code = 117
char = s;code = 115
char = e;code = 101
char = d;code = 100
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char = r;code = 114
char = e;code = 101
char = c;code = 99
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char = o;code = 111
char = r;code = 114
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char = e;code = 101
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char = e;code = 101
char = f;code = 102
char = f;code = 102
char = e;code = 101
char = c;code = 99
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char = s;code = 115
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char = (;code = 40
char = e;code = 101
char = x;code = 120
char = a;code = 97
char = g;code = 103
char = g;code = 103
char = e;code = 101
char = r;code = 114
char = a;code = 97
char = t;code = 116
char = e;code = 101
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char = ;code = 32
char = p;code = 112
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char = a;code = 97
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char = m;code = 109
char = a;code = 97
char = c;code = 99
char = o;code = 111
char = l;code = 108
char = o;code = 111
char = g;code = 103
char = y;code = 121
char = );code = 41
char = .;code = 46
char = ;code = 32
char = B;code = 66
char = a;code = 97
char = s;code = 115
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = o;code = 111
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char = ;code = 32
char = p;code = 112
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char = o;code = 111
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char = p;code = 112
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char = d;code = 100
char = e;code = 101
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char = o;code = 111
char = f;code = 102
char = ;code = 32
char = a;code = 97
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
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result sql = Despite clinical promise, dual-acting activators of PPARalpha and gamma (here termed PPARalpha+gamma agonists) have experienced high attrition rates in preclinical and early clinical development, due to toxicity. In some cases, discontinuation was due to carcinogenic effect in the rat urothelium, the epithelial layer lining the urinary bladder, ureters, and kidney pelvis. Chronic pharmacological activation of PPARalpha is invariably associated with cancer in rats and mice. Chronic pharmacological activation of PPARgamma can in some cases also cause cancer in rats and mice. Urothelial cells coexpress PPARalpha as well as PPARgamma, making it plausible that the urothelial carcinogenicity of PPARalpha+gamma agonists may be caused by receptor-mediated effects (exaggerated pharmacology). Based on previously published mode of action data for the PPARalpha+gamma agonist ragaglitazar, and the available literature about the role of PPARalpha and gamma in rodent carcinogenesis, we propose a mode of action hypothesis for the carcinogenic effect of PPARalpha+gamma agonists in the rat urothelium, which combines receptor-mediated and off-target cytotoxic effects. The proposed mode of action hypothesis is being explored in our laboratories, towards understanding the human relevance of the rat cancer findings, and developing rapid in vitro or short-term in vivo screening approaches to faciliate development of new dual-acting PPAR agonist compounds.

Publication: PPAR Res 2008 ;2008:103167. :doi: 10.1155/2008/103167.
Publication Date: 2008
Study Author(s): Oleksiewicz, Martin B;Southgate, Jennifer;Iversen, Lars;Egerod, Frederikke L;
Institution: Molecular Toxicology, Novo Nordisk A/S, 2760 Maalov, Denmark.
Shortcut link to this study:
Despite clinical promise, dual-acting activators of PPARalpha and gamma (here termed PPARalpha+gamma agonists) have experienced high attrition rates in preclinical and early clinical development, due to toxicity. In some cases, discontinuation was due to carcinogenic effect in the rat urothelium, the epithelial layer lining the urinary bladder, ureters, and kidney pelvis. Chronic pharmacological activation of PPARalpha is invariably associated with cancer in rats and mice. Chronic pharmacological activation of PPARgamma can in some cases also cause cancer in rats and mice. Urothelial cells coexpress PPARalpha as well as PPARgamma, making it plausible that the urothelial carcinogenicity of PPARalpha+gamma agonists may be caused by receptor-mediated effects (exaggerated pharmacology). Based on previously published mode of action data for the PPARalpha+gamma agonist ragaglitazar, and the available literature about the role of PPARalpha and gamma in rodent carcinogenesis, we propose a mode of action hypothesis for the carcinogenic effect of PPARalpha+gamma agonists in the rat urothelium, which combines receptor-mediated and off-target cytotoxic effects. The proposed mode of action hypothesis is being explored in our laboratories, towards understanding the human relevance of the rat cancer findings, and developing rapid in vitro or short-term in vivo screening approaches to faciliate development of new dual-acting PPAR agonist compounds.
PMID: 19197366

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