Author: Li, Ziyu ; Czechtizky, Werngard ; Brummerhop, Harm ; Schaefer, Hans-Ludwig ; Schiffer, Alexander ; Voss, Marc D ; Petry, Stefan ; Rudolph, Christine ; Langer, Thomas

Phosphatidylinositol-5-phosphate 4-kinase, type II, beta (PIP5K2B) is linked to the pathogenesis of obesity, insulin resistance and diabetes. Here, we describe the identification of a novel pyrimidine-2,4-diamine PIP5K2B inhibitor, designated SAR088. The compound was identified by high-throughput screening and subsequently characterized in vitro and in vivo. SAR088 showed reasonable potency, selectivity and physicochemical properties in enzymatic and cellular assays. In vivo, SAR088 lowered blood glucose levels of obese and hyperglycemic male Zucker diabetic fatty rats treated for 3 weeks. Thus, SAR088 represents the first orally available and in vivo active PIP5K2B inhibitor and provides an excellent starting point for the development of potent and selective PIP5K2B inhibitors for the treatment of insulin resistance and diabetes.

01 May 2002·Biochemical PharmacologyQ2 · MEDICINE

HOE 402 lowers serum cholesterol levels by reducing VLDL-lipid production, and not by induction of the LDL receptor, and reduces atherosclerosis in wild-type and LDL receptor-deficient mice

Q2 · MEDICINE

Article

Author: Vivian E.H. Dahlmans ; Hans M.G. Princen ; Oscar L. Volger ; Richard Draijer ; Louis M. Havekes ; Elly C.M. de Wit

Previous rodent studies suggested that the potent hypolipidemic agent 4-amino-2-(4,4-dimethyl-2-oxo-1-imidazolidinyl)pyrimidine-5-N-(trifluoromethyl-phenyl) carboxamide monohydrochloride (HOE 402) is an inducer of the LDL receptor (LDLR). Using wild-type and heterozygous and homozygous LDLR-deficient (LDLR+/0 and LDLR0/0) mice, fed a low or high cholesterol diet, we investigated whether HOE 402 specifically induces the LDLR and whether other pathways are affected. Upon treatment with 0.05% (w/w) HOE 402, the serum cholesterol levels of wild-type, LDLR+/0 and LDLR0/0 mice, were maximally reduced by 53, 56, and 73%, respectively (P<0.05), by reducing levels in very low density-lipoprotein (VLDL), intermediate density-lipoprotein (IDL), and low density-lipoprotein (LDL) cholesterol, whereas high density-lipoprotein (HDL) cholesterol levels were increased. The observations that HOE 402 exhibited no effect on in vivo clearance of 125I-labeled LDL in wild-type mice, and clearly reduced serum cholesterol levels in LDLR0/0 mice, indicate that the LDLR is not the main target for the compound. In wild-type mice, production of VLDL-TG, and cholesterol were reduced by more than 50% by HOE 402 (P<0.05), whereas VLDL apolipoprotein B (ApoB) secretion was unaffected, indicating that HOE 402 treatment changes the size, rather than the number of the secreted VLDL particles. The reduced VLDL production was accompanied by a 22% decreased hepatic cholesterol ester concentration (P<0.05). Additionally, HOE 402 treatment strongly reduced the aortic content of atherosclerotic lesions by 90 and 72% in LDLR+/0 and LDLR0/0 mice, respectively (P<0.01). In conclusion, HOE 402 is a potent cholesterol-lowering compound, which inhibits VLDL production, and consequently attenuates atherosclerosis development.

01 Jan 1996·Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism

Cholesterol lowering action of HOE 402 in the normolipidemic and hypercholesterolemic Golden Syrian hamster

Article

Author: Manfred Schmalz ; Michael Leineweber ; Axel Hoffmann

The potent hypolipidemic activity of HOE 402 (4-amino-2-(4, 4-dimethyl-2-oxo-1-imidazolidinyl)pyrimidine-5-N-(trifluoromethyl-phenyl ) carboxamide monohydrochloride), which was previously demonstrated in rat and rabbit, was investigated in noncholesterol and cholesterol fed male hamsters. In normolipidemic hamsters fed a low cholesterol chow diet containing 0.10% or 0.15% HOE 402 for 3 weeks, the plasma total cholesterol level fell by 13% and 20% respectively, but no effect on hepatic total cholesterol content was detected. Hepatic sterol synthesis was increased 3-fold in hamsters fed 0.15% HOE 402. In hamsters fed a chow diet containing 0.25% cholesterol for 3 weeks, the plasma cholesterol level increased to 226 mg/dl (compared to 123 mg/dl in their chow fed controls) and the liver cholesterol content was 26.2 mg/g compared to 2.3 mg/g in the control group. However, 0.15% HOE 402 led to a 48% reduction and 0.20% HOE 402 to a 80% reduction, in total hepatic cholesterol concentration. There was a 43% fall in plasma cholesterol level being observed with the higher HOE 402 dose. Using the dual isotope plasma ratio method, no inhibition of intestinal cholesterol absorption by HOE 402 was found, either in the noncholesterol fed or in the cholesterol fed hamsters. Cholesterol feeding diminished the whole LDL animal clearance to 393 +/- 17 microliters/h per 100 g animal (control 666 +/- 81 microliters/h per 100 g). When treated with 0.20% HOE 402, the whole animal LDL clearance rate was enhanced 2.3-fold to 824 +/- 66 microliters/h per 100 g. In the hamsters fed 0.25% cholesterol alone whole liver LDL receptor activity was suppressed to 63 +/- 5%, compared to that in the untreated controls (100%). The addition of 0.20% HOE 402 to the cholesterol enriched diet not only reversed this suppression, but resulted in a marked stimulation of liver receptor activity to 165 +/- 15% (whole body LDL receptor activity 141 +/- 10%). These results indicate that HOE 402 exerts its lipid lowering effect by a more direct activation on hepatic LDL receptor activity rather than by an indirect intestinal effect on cholesterol absorption.

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Indication	Highest Phase	Country/Location	Organization	Date
Hyperlipidemias	Phase 2	-	Sanofi	-

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