Gerhard Zoller

Identification and synthesis of novel inhibitors of acetyl-CoA carboxylase with in vitro and in vivo efficacy on fat oxidation.

Acetyl CoA carboxylase isoforms 1 and 2 (ACC1/2) are key enzymes of fat utilization and their inhibition is considered to improve aspects of the metabolic syndrome. To identify pharmacological inhibitors of ACC1/2, a high throughput screen was performed which resulted in the identification of the lead compound 3 ( Gargazanli , G. ; Lardenois , P. ; Frost , J. ; George , P. Patent WO9855474 A1, 1998 ) as a moderate selective ACC2 inhibitor. Optimization of 3 led to 4m ( Zoller , G. ; Schmoll , D. ; Mueller , M. ; Haschke , G. ; Focken , I. Patent WO2010003624 A2, 2010 ) as a submicromolar dual ACC1/2 inhibitor of the rat and human isoforms. 4m possessed favorable pharmacokinetic parameters. This compound stimulated fat oxidation in vivo and reduced plasma triglyceride levels in a rodent model after subchronic administration. 4m is a suitable tool compound for the elucidation of the pharmacological potential of ACC1/2 inhibition.

Benzimidazole-carboxamides as potent and bioavailable stearoyl-CoA desaturase (SCD1) inhibitors from ligand-based virtual screening and chemical optimization

The discovery of potent benzimidazole stearoyl-CoA desaturase (SCD1) inhibitors by ligand-based virtual screening is described. ROCS 3D-searching gave a favorable chemical motif that was subsequently optimized to arrive at a chemical series of potent and promising SCD1 inhibitors. In particular, compound SAR224 was selected for further pharmacological profiling based on favorable in vitro data. After oral administration to male ZDF rats, this compound significantly decreased the serum fatty acid desaturation index, thus providing conclusive evidence for SCD1 inhibition in vivo by SAR224.

Discovery and pharmacological characterization of SAR707 as novel and selective small molecule inhibitor of stearoyl-CoA desaturase (SCD1)

Stearoyl-CoA desaturase (SCD1) is linked to the pathogenesis of obesity, dyslipidemia and type 2 diabetes. It is the rate-limiting enzyme in the synthesis of monounsaturated 16:1 n-7 and 18:1 n-9 fatty acyl-CoAs and catalyzes an essential part of lipogenesis. Here, we describe the identification, in vitro properties and in vivo efficacy of a novel class of heterocyclic small molecule hexahydro-pyrrolopyrrole SCD1 inhibitors. SAR707, a compound representative for the series, was optimized to high in vitro potency, selectivity and favorable overall properties in enzymatic and cellular assays. In vivo, this compound reduced serum desaturation index, decreased body weight gain and improved lipid parameters and blood glucose levels of obese Zucker diabetic fatty rats treated for 4 weeks in a chronic study. In parallel, fissures of the eye lid, alopecia and inflammation of the skin were observed from day 11 on in all animals treated with the same metabolically active dose. In summary, we described in vitro and in vivo properties of a novel, potent and selective SCD1 inhibitor that improved body weight, blood glucose and triglycerides in an animal model of obesity, type 2 diabetes and dyslipidemia. However, the favorable in vivo properties of systemic SCD1 inhibition shown in our study were accompanied by dose-dependently occurring adverse target-related effects observed in skin. Thus, systemic SCD1 inhibition by small molecules might therefore not represent a feasible approach for the treatment of chronic metabolic diseases.

From a peptide lead to an orally active peptidomimetic fibrinogen receptor antagonist

Antagonists of the platelet fibrinogen receptor (GP IIb/IIIa receptor) are expected to be a new promising class of antithrombotic agents. The binding of fibrinogen to the fibrinogen receptor depends on an Arg-Gly-Asp-Ser (RGDS) tetrapeptide recognition motif. Structural modifications of the RGDS lead have led to the discovery of a non-peptide RGD mimetic GP IIb/IIIa antagonist20 (S 1197). Compound20 inhibits dose-dependently and reversibly human platelet aggregation. Modeling studies based on structure-activity data revealed the following structural features of the drug as important for receptor binding: the amidino group, the carboxylate group, hydrophobic substitutions at the carboxyl-terminus and at the side chain carrying the positive charge, the carboxyl-terminal NH group of the β-amino acid as a hydrogen bond donor and one oxygen atom of the hydantoin as a hydrogen bond acceptor. The ethyl ester prodrug of20 (S 5740) is an orally active antithrombotic agent which has the potential to be used to treat and prevent thrombotic diseases in humans.