Alberto Cerri

Asymmetric N-(3,3-diphenylpropyl)aminoalkyl esters of 4-aryl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acids with antihypertensive activity

Abstract A series of asymmetric 4-aryl-1,4-dihydropyridine-3,5-dicarboxylates characterized by the presence of a 3,3-diphenyl-propylamino moiety in one of the ester groups were synthesized. They exhibited remarkable antihypertensive activity in spontaneously hypertensive rats as well as affinity for the 1,4-dihydropyridines binding site labelled by 3 H -nitrendipine in the calcium channel. Introduction of this bulky and lipophilic amine confers to the whole series an elevated level of antihypertensive activity and a long duration of action, a structure-dependent modulation of the activity being found only in the subset characterized by the presence of a branched propylene bridge between the ester and the amino groups. The presence of the amino group is essential for oral activity. Out of this series, compound 9u (Rec 15/2375-lercanidipine) was selected for clinical development and obtained marketing authorization as an antihypertensive in several countries.

A GENERAL, 1+4 APPROACH TO THE SYNTHESIS OF 3(5)-SUBSTITUTED PYRAZOLES FROM ALDEHYDES

Abstract A new, one-pot preparation of 3(5)-substituted-1H-pyrazole is described that employs Horner-Emmons reaction of aldehydes with dianion of novel phosphonate 1 and proceeds through cyclization of N-sodium salt of α,β-unsaturated tosylhydrazones 2 .

Novel Analogues of Istaroxime, a Potent Inhibitor of Na+,K+-ATPase: Synthesis and Structure−Activity Relationship†

We report the synthesis and biological properties of novel inhibitors of the Na(+),K(+)-ATPase as positive inotropic compounds. Following our previously described model from which Istaroxime was generated, the 5alpha,14alpha-androstane skeleton was used as a scaffold to study the space around the basic chain of our lead compound. Some compounds demonstrated higher potencies than Istaroxime on the receptor and the (E)-3-[(R)-3-pyrrolidinyl]oxime derivative, 15, was the most potent; as further confirmation of our model, the E isomers of the oxime are more potent than the Z form. The compounds tested in the guinea pig model induced positive inotropic effects, which are correlated to the in vitro inhibitory potency on the Na(+),K(+)-ATPase. The finding that all tested compounds resulted less proarrhythmogenic than digoxin, a currently clinically used positive inotropic agent, suggests that this could be a feature of the 3-aminoalkyloxime derivative class of 5alpha,14alpha-androstane.

Novel analogues of Istaroxime, a potent inhibitor of Na+,K+-ATPase: Synthesis, structure–activity relationship and 3D-quantitative structure–activity relationship of derivatives at position 6 on the androstane scaffold

We report the synthesis and biological properties of novel analogues of Istaroxime acting as positive inotropic compounds through the inhibition of the Na(+),K(+)-ATPase. We explored the chemical space around the position 6 of the steroidal scaffold by changing the functional groups at that position and maintaining a basic oximic chain in position 3. Some compounds showed inhibitory potencies of the Na(+),K(+)-ATPase higher than Istaroxime and many of the compounds tested in vivo were safer than digoxin, the classic digitalis compound currently used for the treatment of congestive heart failure as inotropic agent. The 3D-QSAR analyses using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods have been successfully applied to a set of 63 androstane derivatives as Na(+),K(+)-ATPase inhibitors. The contour plots provide many useful insights into relationships between structural features and inhibitory potency.

Novel fragmentation reactions of bafilomycin A1

Abstract Two novel fragmentations of the skeletal back bone of bafilomycin A 1 are reported. These reactions occur under mild conditions and afford new bafilomycin analogues lacking 4 and 8 carbon atoms of the tetrahydropyran ring, respectively.

An unusually facile preparation of 21-alkoxyderivatives of bafilomycin A1

Abstract 21-alkoxy derivatives of bafilomycin A 1 can be obtained easily by treatment of bafilomycin A 1 with linear, primary alcohols in the presence of an aqueous solution of oxalic acid. Reaction proceeds with complete retention of configuration.

Simplified Digitalis-like Compounds acting on Na+, K+-ATPase

Digitalis compounds are used in the treatment of congestive heart failure as positive inotropic agents; their action is mainly due to the inhibition of Na+,K+-ATPase. A well-known drawback is their arrhythmogenic potential. Attempts to find safer digitalis-like compounds by means of molecular simplifications of the typical 5β,14β-steroidal skeleton, which appeared in the medicinal chemistry literature from 1990 until 2002, are briefly reviewed. Several novel achievements were obtained in order to better understand the requisites of the digitalis binding site on Na+, K+-ATPase. Only minor simplification, such as cleavage of the D ring of the digitalis skeleton, could preserve the desired inotropic activity, while highly simplified digitalis-like compounds failed to give sufficiently high inotropic potency, even in the presence of a powerful pharmacophore, such as the O-aminoalkyloxime group.

Synthesis of 6′- and 7′-(3-furylmethyl) derivatives of endo-1′,2′,3′,4′-tetrahydro-1′,4′-ethano-2′-naphthylethanol with potential activity on Na+, K+-ATPase

The 6′- and 7′-(3-furylmethyl) derivatives of endo-1′,2′,3′,4′-tetrahydro-1′,4′-ethano-2′-naphthylethanol 1 have been synthesized as simplified analogues of digitoxigenin. The skeleton was built starting from 3,4-dihydro-1,4-ethanonaphthalen-2(1H)-one 2; the substituents were introduced by a Wittig–Horner reaction followed by a highly stereoselective hydrogenation to form the endo derivative 4 and successive acylation with 3-furoyl chloride to give the intermediates 8a and 8b. Tested compounds showed only moderate activity on the Na+, K+-ATPase, with IC50 values in the 10–4 mol dm–3 range.