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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.

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.

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.

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.

The alkoxide-catalyzed addition of alcohols to α-chloroacrylonitrile at -35°C gives rise to 3-alkoxy-2-chloropropanenitriles; at 0–5°C with excess alkyl 3-alkoxy-2-chloropropanimidates are obtained. The yields of 3 or 4 decrease with increasing pKa values of the alcohols. In the base-catalyzed addition of phenols 5 to 1, a temperature-dependent addition equilibrium is set up in which the position of equilibrium is shifted in favour of the addition products with increasing pKa values of 5. The 3-alkoxy-2-chloropropanoates, which are readily accessible by hydrolysis of 4, react smoothly with sodium azide in the presence of a phase transfer catalyst to furnish the 3-alkoxy-2-azidopropanoates. Starting from benzyl 2-azido-3-benzyloxy-propanoate (10b), the specific syntheses of DL-serine (14), DL-serine hydrochloride (14·HCl), DL-serine methyl ester hydrochloride (13a·HCl), 0-benzyl-DL-serine (12b), and 0-benzyl-DL-serine benzyl ester hydrochloride (11b·HCl) are possible by variation of the hydrogenation conditions.

Antagonists of the platelet fibrinogen receptor (GP IIb/IIIa receptor) are expected to be a promising new 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 antagonist 44 (S 1197). Compound 44 inhibited, in a dose dependent and reversible manner, human and dog platelet aggregation as well as 125I-fibrinogen binding to ADP-activated human gel filtered platelets and isolated GP IIb/IIIa with K(i) values of 9 nM and 0.17 nM, respectively. A pharmacophore mapping procedure with QXP and a 3D-QSAR analysis applying the GRID/GOLPE methodology yielded a stable, rather predictive model and revealed structural features which are important for binding. Hydrophobic substitutions both at the hydantoin nucleus and at the C-terminus increase the affinity toward the fibrinogen receptor. The crystalline ethyl ester prodrug 48 (HMR 1794) is an orally active antithrombotic agent which is a promising drug candidate for the treatment of thrombotic diseases in humans.

The alkoxide-catalyzed addition of alcohols to α-chloroacrylonitrile at -35°C gives rise to 3-alkoxy-2-chloropropanenitriles; at 0–5°C with excess alkyl 3-alkoxy-2-chloropropanimidates are obtained. The yields of 3 or 4 decrease with increasing pKa values of the alcohols. In the base-catalyzed addition of phenols 5 to 1, a temperature-dependent addition equilibrium is set up in which the position of equilibrium is shifted in favour of the addition products with increasing pKa values of 5. The 3-alkoxy-2-chloropropanoates, which are readily accessible by hydrolysis of 4, react smoothly with sodium azide in the presence of a phase transfer catalyst to furnish the 3-alkoxy-2-azidopropanoates. Starting from benzyl 2-azido-3-benzyloxy-propanoate (10b), the specific syntheses of DL-serine (14), DL-serine hydrochloride (14·HCl), DL-serine methyl ester hydrochloride (13a·HCl), 0-benzyl-DL-serine (12b), and 0-benzyl-DL-serine benzyl ester hydrochloride (11b·HCl) are possible by variation of the hydrogenation conditions.