The ubiquitin-proteasome pathway plays a central role in regulation of the production and destruction of cellular proteins. These pathways mediate proliferation and cell survival, particularly in malignant cells. The successful development of the 20S human proteasome inhibitor bortezomib for the treatment of relapsed and refractory multiple myeloma has established this targeted intervention as an effective therapeutic strategy. Herein, the potent, selective, and orally bioavailable threonine-derived 20S human proteasome inhibitor that has been advanced to preclinical development, [(1R)-1-[[(2 S,3 R)-3-hydroxy-2-[(6-phenylpyridine-2-carbonyl)amino]-1-oxobutyl]amino]-3-methylbutyl]boronic acid 20 (CEP-18770), is disclosed.

Alcohols and 1,2-diols oxidation by o-iodoxybenzoic acid (IBX) has been examined by 1H-NMR spectroscopy. Reversible formation of reactive intermediates, iodic esters 5, has been observed, and their structures in DMSO-d 6 solution have been defined as 10-I-4 axial alkoxyiodinane oxides by comparison of the chemical shift difference data with those obtained for Dess−Martin periodinane (DMP)−alcoholate and −diolate adducts. The dichotomous behavior exhibited by IBX and DMP with 1,2-diols can be explained in terms of the different architecture of the reactive intermediates involved in the oxidation. With aliphatic alcohols, kinetic evidences support a two-step reaction mechanism involving a fast pre-equilibrium step leading to 5, followed by a rate-determining disproportionation step. With electronically activated benzyl alcohol, the attainment of pre-equilibrium is largely dependent on initial water concentration as a consequence of a particularly high k 2 value. The influence of the alcohol structure on measured equilibrium (K eq) and rate constants (k 2) and the effect of water on the overall reaction rate are discussed.

The novel Na ϩ /K ϩ -ATPase inhibitor (E,Z)-3-((2-aminoethoxy)-imino)androstane-6,17-dione hydrochloride (PST2744) was characterized for its inotropic and toxic properties. Inhibition potency on dog kidney Na ϩ /K ϩ -ATPase was comparable (0.43 M) to that of digoxin (0.45 M). PST2744 concentration-dependently increased force of contraction in guinea pig atria and twitch amplitude in isolated guinea pig myocytes; in the latter, aftercontractions developed significantly less than with digoxin. Intravenous infusion of 0.2 mg/kg/min PST2744 in anesthetized guinea pigs exerted an immediate and long-lasting inotropic effect (ED 80 of 1.89 Ϯ 0.37 mg/kg) without causing lethal arrhythmias up to a cumulative dose of 18 mg/kg. Conversely, an equieffective infusion of digoxin (0.016 mg/kg/min; ED 80 of 0.32 mg/kg) caused lethal arrhythmias at a cumulative dose of 0.81 mg/kg. At a higher rate (0.4 mg/kg/min), PST2744 induced lethal arrhythmias, with a lethal dose/ED 80 ratio significantly greater than digoxin (20.2 Ϯ 6.3 versus 3.23 Ϯ 0.55, p Ͻ 0.05). Decay of the inotropic effect (t 1/2 , min) was significantly faster for PST2744 (6.0 Ϯ 0.39) than for digoxin (18.3 Ϯ 4.5, p Ͻ 0.05). In anesthetized dogs, PST2744 dose-dependently increased maximum velocity of pressure rise (ϩdP/dt max ) in the range 32 to 500 g/kg i.v. and was safer than digoxin. In conscious dogs with a healed myocardial infarction, PST2744 significantly increased resting values of ϩdP/dt max , left ventricular pressure, and SPB, and increased ϩdP/dt max throughout treadmill exercise while reverting the increase in left ventricular end diastolic pressure seen in control animals. Digoxin significantly decreased basal heart rate, while not affecting the hemodynamic response to exercise. Thus, PST2744 represents a new class of Na ϩ /K ϩ -ATPase inhibitors endowed with inotropic activity comparable with that of digitalis but having greater safety.Improvement of heart failure (HF) treatment remains a major medical challenge for the coming years. Despite achievement of considerable progress during the last two decades, none of the available therapeutic agents is fully satisfactory, and HF remains a disease with a poor prognosis (Kannel, 2000). The goal of ameliorating quality of life, exercise capability, and survival is only partially met by angiotensin-converting enzyme inhibitors, diuretics, vasodilators, glycosides, and ␤-blocking agents, regardless of their being used in combined therapy (Consensus Recommendations for the Management of Chronic Heart Failure, 1999). Therefore, the need still remains for novel drugs able to increase workload tolerance and to reduce morbidity and mortality. Worsening of survival found with chronic administration of inotropic agents that increase intracellular cAMP (phosphodiesterase inhibitors and sympathomimetic amines) (The Xamoterol in Severe Heart Failure Study Group, 1990;Packer et al., 1991;Cohn et al., 1998) and the well known arrhythmogenic effects of cardiac glycosides have led to the general view that drug-i...

The design, synthesis, and biological properties of novel inhibitors of the Na(+),K(+)-ATPase as potential positive inotropic compounds are reported. Following our model of superposition between cassaine and digitoxigenin, digitalis-like activity has been elicited from a non-digitalis steroidal structure by suitable modifications of the 5alpha,14alpha-androstane skeleton. The strong hydrophobic interaction of the digitalis or cassaine polycyclic cores can be effectively obtained with the androstane skeleton taken in a reversed orientation. Thus, oxidation of C-6 and introduction in the C-3 position of the potent pharmacophoric group recently introduced by us, in the 17 position of the digitalis skeleton, namely, O-(omega-aminoalkyl)oxime, led to a series of substituted androstanes able to inhibit the Na(+),K(+)-ATPase, most of them with an IC(50) in the low micromolar level, and to induce a positive inotropic effect in guinea pig. Within this series, androstane-3,6,17-trione (E,Z)-3-(2-aminoethyl)oxime (22b, PST 2744) induced a strong positive inotropic effect while being less arrhythmogenic than digoxin, when the two compounds were compared at equiinotropic doses.

A new three-dimensional model for the relative binding mode of cassaine 1 and digitoxigenin 2 at the digitalis receptor site is proposed on the basis of the structural and conformational similarities among 1, 2 and its 14,15-seco analogues 3 and 4. Accordingly, the speculation that also 17alpha-substituted derivatives of the digitalis 5beta,14beta-androstane skeleton could efficiently bind to the Na+,K+-ATPase receptor is put forward and verified through the synthesis of some related compounds. The binding affinity shown by 2-(N,N-dimethylamino)ethyl 3beta, 14-dihydroxy-5beta,14beta-androstane-17alpha-acrylate 6 (IC50 = 5.89 microM) and, much more significantly, by the corresponding 14, 15-seco-14-oxo derivative 9 (IC50 = 0.12 microM) substantiates the new hypothesis and opens new prospects to the design of novel inhibitors of Na+,K+-ATPase as potential positive inotropic compounds.