Victor Segarra

CoMFA of benzyl derivatives of 2,1,3-benzo and benzothieno[3,2-a]thiadiazine 2,2-dioxides : clues for the design of phosphodiesterase 7 inhibitors

A CoMFA study of benzo- and benzothienothiadiazines derivatives as phosphodiesterase 7 inhibitors has been carried out in order to determine the factors required for the activity of these compounds and also for the selectivity versus other phosphodiesterase isoenzymes. This methodology is employed to gain clues on the design of new fused thiadiazines with improved activity and selectivity on phosphodiesterase 7. Using the information achieved from the three CoMFA models, new structures have been designed in silico and their inhibitory activity on phosphodiesterase 7 was predicted.

Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinol esters as potent and long-acting muscarinic antagonists with potential for minimal systemic exposure after inhaled administration: identification of (3R)-3-{[hydroxy(di-2-thienyl)acetyl]oxy}-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (aclidinium bromide).

The objective of this work was to discover a novel, long-acting muscarinic M(3) antagonist for the inhaled treatment of chronic obstructive pulmonary disease (COPD), with a potentially improved risk-benefit profile compared with current antimuscarinic agents. A series of novel quaternary ammonium derivatives of (3R)-quinuclidinol esters were synthesized and evaluated. On the basis of its overall profile, (3R)-3-{[hydroxy(di-2-thienyl)acetyl]oxy}-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (aclidinium bromide) emerged as a candidate for once-daily maintenance treatment of COPD. This compound is a potent muscarinic antagonist, with long duration of action in vivo, and was found to have a rapid hydrolysis in human plasma, minimizing the potential to induce class-related systemic side effects. Aclidinium bromide is currently in phase III development for maintenance treatment of patients with COPD.

Phosphodiesterase inhibitory properties of losartan. Design and synthesis of new lead compounds.

A 4-centre PDE4 pharmacophore search has been carried out in several 3D-databases containing compounds belonging to different therapeutic areas. Losartan, an angiotensin-II antagonist, has been identified as a new lead compound for developing PDE4 inhibitors. New families of compounds derived from losartan has been synthesized and their PDE inhibition has been measured.

Setup and validation of shake-flask procedures for the determination of partition coefficients (logD) from low drug amounts.

Several procedures based on the shake-flask method and designed to require a minimum amount of drug for octanol-water partition coefficient determination have been established and developed. The procedures have been validated by a 28 substance set with a lipophilicity range from -2.0 to 4.5 (logD7.4). The experimental partition is carried out using aqueous phases buffered with phosphate (pH 7.4) and n-octanol saturated with buffered water and the analysis is performed by liquid chromatography. In order to have accurate results, four procedures and eight different ratios between phase volumes are proposed. Each procedure has been designed and optimized (for partition ratios) for a specific range of drug lipophilicity (low, regular and high lipophilicity) and solubility (high and low aqueous solubility). The procedures have been developed to minimize the measurement in the octanolic phase. Experimental logD7.4 values obtained from different procedures and partition ratios show a standard deviation lower than 0.3 and there is a nice agreement when these values are compared with the reference literature ones.

Synthesis and biological evaluation of 2,5-dihydropyrazolo[4,3-c]quinolin-3-ones, a novel series of PDE 4 inhibitors with low emetic potential and antiasthmatic properties

A novel series of 2,5-dihydropyrazolo[4,3-c]quinolin-3-ones has been prepared. These compounds showed good PDE 4 inhibitory activity and weak affinity for roliprams binding site. They also exhibited a good anti-inflammatory profile without emetic side effects.

1-, 3- and 8-substituted-9-deazaxanthines as potent and selective antagonists at the human A2B adenosine receptor

A large series of piperazin-, piperidin- and tetrahydroisoquinolinamides of 4-(1,3-dialkyl-9-deazaxanthin-8-yl)phenoxyacetic acid were prepared through conventional or multiple parallel syntheses and evaluated for their binding affinity at the recombinant human adenosine receptors, chiefly at the hA(2B) and hA(2A) receptor subtypes. Several ligands endowed with high binding affinity at hA(2B) receptors, excellent selectivity over hA(2A) and hA(3) and a significant, but lower, selectivity over hA(1) were identified. Among them, piperazinamide derivatives 23 and 52, and piperidinamide derivative 69 proved highly potent at hA(2B) (K(i)=11, 2 and 5.5 nM, respectively) and selective towards hA(2A) (hA(2A)/hA(2B) SI=912, 159 and 630, respectively), hA(3) (hA(3)/hA(2B) SI=>100, 3090 and >180, respectively) and hA(1) (hA(1)/hA(2B) SI=>100, 44 and 120, respectively), SI being the selectivity index. A number of selected ligands tested in functional assays in vitro showed very interesting antagonist activities and efficacies at both A(2A) and A(2B) receptor subtypes, with pA(2) values close to the corresponding pK(i)s. Structure-affinity and structure-selectivity relationships suggested that the binding potency at the hA(2B) receptor may be increased by lipophilic substituents at the N4-position of piperazinamides and that an ortho-methoxy substituent at the 8-phenyl ring and alkyl groups at N1 larger than the ones at N3, in the 9-deazaxanthine ring, may strongly enhance the hA(2A)/hA(2B) SI.

Heterocyclic-fused 3(2H)-pyridazinones as potent and selective PDE IV inhibitors : Further structure-activity relationships and molecular modelling studies

Abstract A novel group of heterocyclic-fused 3(2H)-pyridazinones were synthesized and evaluated as PDE III and PDE IV inhibitors and their affinity for 3 H Rolipram high affinity binding site was determined. The obtained data demonstrated that some of the new compounds are endowed with potent and selective PDE IV inhibitory activity and greatly attenuated affinity for the Rolipram high affinity binding site that seems to be responsible for unwanted effects. Theoretical calculations, performed on representative compounds, demonstrated the presence of three hydrogen-bonding acceptor regions, of which one looks quite different with respect to literature compounds. This finding could explain the different pharmacological profile of the title compounds with respect to the analogs reported in the literature.

Synthesis and evaluation of quinazoline derivatives as phosphodiesterase 7 inhibitors

The latest scientific findings concerning PDE7 and PDE4 inhibition suggest that selective small-molecule inhibitors of both enzymes could provide a novel approach to treat a variety of immunological diseases. In this context, we describe a new series of quinazoline derivatives from quinazolin-4-thiones which include a substituted biphenyl fragment. Some of these compounds show inhibitory potencies at sub-micromolar levels against the catalytic domain of PDE7.

Synthesis and Evaluation of Some Pyrazolo[3,4-d]pyridazinones and Analogues as PDE 5 Inhibitors Potentially Useful as Peripheral Vasodilator Agents

A series of pyrazolo[3,4-d]pyridazinones and analogues, potentially useful as peripheral vasodilators, were synthesized and evaluated as inhibitors of PDE5 extracted from human platelets. Several of them showed IC 50 values in the range 0.14-1.4 μM. A good activity and selectivity profile versus PDE6 was found for compound 11e (6-benzyl-3-methyl-1-isopropyl-4-phenylpyrazolo[3,4-d]pyridazin-7(6H)-one). Structure-activity relationship studies demonstrated the essential role played by the benzyl group at position-6 of the pyrazolopyridazine system. Other types of pyridazinones fused with five and six membered heterocycles (pyrrole, isoxazole, pyridine and dihydropyridine), as well as some open models were prepared and evaluated. Besides the pyrazole, the best fused systems proved to be isoxazole and pyridine.

1,7-Naphthyridine 1-Oxides as Novel Potent and Selective Inhibitors of p38 Mitogen Activated Protein Kinase

The design, synthesis, and ability to inhibit p38α MAP kinase by a novel series of naphthyridine N-oxides will be described. Some of these compounds showed a significant reduction in the LPS-induced TNFα production in human whole blood. Structure-activity relationship studies revealed that N-oxide oxygen was essential for activity and was probably a determinant factor for its marked selectivity against other related kinases. After an extensive SAR exercise, several compounds from this series were identified as very potent p38α inhibitors. In vivo efficacy of some derivatives was demonstrated to reduce TNFα levels in an acute murine model of inflammation (ED(50) = 0.5 mg/kg in LPS-induced TNFα production when dosed orally 1.5 h prior to LPS administration). The oral efficacy was further demonstrated in a chronic model of adjuvant arthritis in rats with established disease when administered orally (ED(50) < 1 mg/kg).