Aldosterone is a hormone that exerts manifold deleterious effects on the kidneys, blood vessels, and heart which can lead to pathophysiological consequences. Inhibition of the mineralocorticoid receptor (MR) is a proven therapeutic concept for the management of associated diseases. Use of the currently marketed MR antagonists spironolactone and eplerenone is restricted, however, due to a lack of selectivity in spironolactone and the lower potency and efficacy of eplerenone. Several pharmaceutical companies have implemented programs to identify drugs that overcome the known liabilities of steroidal MR antagonists. Herein we disclose an extended SAR exploration starting from cyano-1,4-dihydropyridines that were identified by high-throughput screening. Our efforts led to the identification of a dihydronaphthyridine, BAY 94-8862, which is a potent, selective, and orally available nonsteroidal MR antagonist currently under investigation in a clinical phase II trial.

The physicochemical characterization of MS‐325 [trisodium {4‐(R)‐[(4,4‐diphenylcyclohexyl)phosphanooxymethyl]‐3,6,9‐triaza‐3,6,9‐tris(methoxycarbonyl)undecanedioato}gadolinium(III)], a new derivative of Gd‐DTPA {Magnevist®: dimeglumin [{3,6,9‐triaza3,6,9‐tris(methoxycarbonyl)undecanedioato}gadolinium(III)], presented as a potentially useful angiographic contrast agent, was carried out in various media. Water solution, protein‐containing solution, phosphorylated metabolites solution, and Zn2+‐containing solution were investigated using different NMR techniques such as water 1H nuclear magnetic relaxation rates, water 17O transverse relaxation rates, and 31P longitudinal relaxation rates of phosphorylated metabolites. The proton relaxivity of MS‐325 in water was found to be higher than that of the parent compound Gd‐DTPA; this can be attributed to the longer rotational correlation time (τR) of the hydrated complex, and possibly to an apparently shorter mean distance (r) between the protons of the coordinated water molecule and the gadolinium ion. The kinetic and thermodynamic stability of MS‐325 in solutions containing phosphorylated metabolites (ATP, phosphocreatine and inorganic phosphate) were measured by 31P relaxation rate analysis and found to be higher than for Gd‐DTPA. Similarly, the Zn2+ transmetallation process studied by proton relaxometry is slower than for the same reference compound. Finally, an analysis of the noncovalent binding of MS‐325 to serum proteins by proton relaxometry showed that MS‐325 interacts with human serum albumin (HSA) and that the association constant of this interaction is equal to 6100 ± 2130 M−1. A peak relaxivity of approx. 50 s−1mM−1 was determined at 25 MHz for the protein‐bound paramagnetic complex. This value is lower than the maximal relaxivity predicted for a paramagnetic center totally immobilized at the surface of the protein.

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A convenient synthesis of disodium S-[4-(4-ethoxybenzyl)-3,6,9-tris[(carboxy-kappaO)methyl]-3,6,9-triazaundecandioato)(5-)-kappa(3)N(3)(),N(6)(),N(9)(),kappa(2)O(1)(),O(11)()]gadolinate(2-) (Gd-EOB-DTPA), 1, is reported. This water-soluble complex is presently undergoing phase III clinical trials as a liver-specific contrast agent for magnetic resonance imaging (MRI). The thermodynamic complex stability constant of 1 and the acid dissociation constants of the ligand have been determined as well as the stability constant of the calcium complex Ca-EOB-DTPA (2), which is used as an additive in the pharmaceutical formulation of the contrast agent. The solid-state structure of the ligand S-4-(4-ethoxybenzyl)-3,6,9-tris(carboxylatomethyl)-3,6,9-triazaundecanedioic acid (H(5)EOB-DTPA), 3, has been elucidated in a single crystal X-ray diffraction study. Additionally, HPLC evidence is given that the enantiomerically pure ligand forms two diastereomeric gadolinium complexes in a 65:35 ratio. The kinetics of isomerization of the isolated diastereomers-as dependent on pH and temperature-has been investigated, and thus, the activation energy for the interconversion of these isomers has been estimated to be 75.3 kJ mol(-1). Finally, the structures of the two components of 1 are discussed in terms of four possible diastereomers.

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