Sonia Laneri

Research on heterocyclic compounds, XLI. 2-Phenylimidazo[1,2-b]pyridazine-3-acetic derivatives: synthesis and anti-inflammatory activity

Abstract The synthesis of a group of 2-phenylimidazo[1,2-b]pyridazine-3-acetic esters and acids is described. The structures of the new compounds are supported by 1 H-NMR spectra. These compounds were tested in vivo for their anti-inflammatory, analgesic and ulcerogenic activity. All new compounds showed remarkable anti-inflammatory action in the carrageenan rat paw oedema (one third of that for indomethacin) but no significant analgesic activity in the acetic acid writhing test together with negligible ulcerogenic action, and were also found to be lacking inhibitory activity on cyclooxygenase in vitro.

Research on heterocyclic compounds. XXXII. Synthesis and cyclooxygenase-independent antiinflammatory and analgesic activity of imidazo[1,2-a]pyrimidine derivatives

Abstract The synthesis of a group of imidazo[1,2-a]pyrimidine-2-carboxylic esters, acids and amides is described. The structures of the new compounds are supported by 1H- and 13C-NMR spectra. These compounds were tested in vivo for their antiinflammatory and analgesic activities as well as for their ulcerogenic action. The ester 5b, the acid 6c and the amide 7a showed antiinflammatory action in the rat paw edema ( ∼1 3 x indomethacin ), while almost all compounds displayed significant analgesic activity in the acetic acid writhing test, particularly the 5-chloro-7-methyl derivatives 5a, 6a and 7a ( ∼1 5 x indomethacin ). All new compounds were found to be lacking in inhibitory activity on cyclooxygenase in vitro.

Ionized Prodrugs of Dehydroepiandrosterone for Transdermal lontophoretic Delivery

AbstractPurpose. The aim of this work was to synthesize ionized dehydroepiandrosterone (DHEA) prodrugs with higher water solubility, useful for iontophoretic transdermal application. Methods. The synthesized derivatives were characterized and tested for sensitivity to chemical and enzymatic hydrolysis. Solid state and solution stability was also determined. Transdermal iontophoretic anodal transport in vitro was studied using excised rabbit skin. Results. Two DHEA ionized prodrugs were synthesized: PRO1, a primary amine derivative, and PRO2, a quaternary ammonium salt. The two derivatives possess higher water solubility and lower octanol/saline partition coefficients than DHEA. Prodrugs were sensitive to enzymatic hydrolysis; in particular the primary amine was hydrolyzed faster than the quaternary salt by esterase from porcine liver in vitro. Transdermal flux of the two prodrugs was slightly higher than the parent drug. In the case of passive diffusion, only DHEA was found in the receptor compartment, indicating the complete breakdown of the prodrug in the skin. Current application gave higher drug flux and a significant amount of prodrug was found in the receptor. Conclusions. The use of ionized prodrugs of DHEA can increase the flux attainable during transdermal anodal iontophoresis by up to 7 times, but they are useful for passive transport as well.

Research on heterocyclic compounds — Part XXXIX. 2-Methylimidazo[1,2-a]pyrimidine-3-carboxylic derivatives: Synthesis and antiinflammatory activity

Abstract The synthesis of a group of 2-methylimidazo[1,2- a ]pyrimidine-3-carboxylic esters, acids and amides is described. The structures of new compounds are supported by 1 H and 13 C NMR spectra. These compounds were tested in vivo for their antiinflammatory, analgesic and ulcerogenic activity. Eight new compounds out of fifteenshowed remarkable dose-dependent antiinflammatory action in the carrageenan rat paw edema (1/2–1/3 × indomethacin) but weak analgesic activity in the acetic acid writhing test together with negligible ulcerogenic action. The new compounds were found to be lacking in inhibitory activity on cyclooxygenase in vitro.

Allosteric modulators of human A2B adenosine receptor.

BACKGROUND Among adenosine receptors (ARs) the A2B subtype exhibits low affinity for the endogenous agonist compared with the A1, A2A, and A3 subtypes and is therefore activated when concentrations of adenosine increase to a large extent following tissue damages (e.g. ischemia, inflammation). For this reason, A2B AR represents an important pharmacological target. METHODS We evaluated seven 1-benzyl-3-ketoindole derivatives (7-9) for their ability to act as positive or negative allosteric modulators of human A2B AR through binding and functional assays using CHO cells expressing human A1, A2A, A2B, and A3 ARs. RESULTS The investigated compounds behaved as specific positive or negative allosteric modulators of human A2B AR depending on small differences in their structures. The positive allosteric modulators 7a,b and 8a increased agonist efficacy without any effect on agonist potency. The negative allosteric modulators 8b,c and 9a,b reduced agonist potency and efficacy. CONCLUSIONS A number of 1-benzyl-3-ketoindole derivatives were pharmacologically characterized as selective positive (7a,b) or negative (8c, 9a,b) allosteric modulators of human A2B AR. GENERAL SIGNIFICANCE The 1-benzyl-3-ketoindole derivatives 7-9 acting as positive or negative allosteric modulators of human A2B AR represent new pharmacological tools useful for the development of therapeutic agents to treat pathological conditions related to an altered functionality of A2B AR.

Modulation of A2B Adenosine Receptor by 1-Benzyl-3-ketoindole Derivatives

We have disclosed a series of 1-benzyl-3-ketoindole derivatives acting as either positive or negative modulators of the human A(2B) adenosine receptor (A(2B) AR) depending on small differences in their side chain. The new compounds were designed taking into account structural similarities between AR antagonists and ligands of the GABA(A)/benzodiazepine receptor. All compounds resulted totally inactive at A(2A) and A₃ ARs and showed small (8a,b) or none (7a,b, 8c and 9a,b) affinity for A₁ AR. When tested on A(2B) AR-transfected CHO cells, 7a,b and 8a acted as positive modulators, whereas 8b,c and 9a,b acted as negative modulators, enhancing or weakening the NECA-induced increase of cAMP levels, respectively. Compounds 7-9 might be regarded as useful biological and pharmacological tools to explore the therapeutic potential of A(2B) AR modulators, while their 3-ketoindole scaffold might be taken as a reference to design new analogs.

In-vitro and in-vivo evaluation of oligoethylene esters as dermal prodrugs of 18β-glycyrrhetic acid

Novel polyoxyethylene esters of 18 β‐glycyrrhetic acid (GA) were synthesized and evaluated as potential dermal prodrugs. The permeation of these prodrugs (1a‐e) was studied in‐vitro, using excised human skin membranes (SCE; stratum corneum/epidermis) mounted in Franz type cells, and in‐vivo, evaluating the ability of these compounds to inhibit methyl nicotinate (MN)‐induced skin erythema in healthy human subjects. All the esters synthesized showed a good water stability, while the enzymatic hydrolysis rate was significantly affected by the length of the polyoxyethylenic chain used as promoiety. In in‐vitro percutaneous absorption studies, only esters 1b and 1c (respectively triethylen‐ and tetraethylenglycol derivatives) showed an increased flux through SCE membranes compared with GA. Furthermore, we observed an appreciable and sustained in‐vivo topical anti‐inflammatory activity of esters 1b and 1c compared with the parent drug.

β-Defensins in the Fight against Helicobacter pylori

Antimicrobial peptides (AMPs) play a pivotal role in the innate immune responses to Helicobacter pylori (Hp) in humans. β-Defensins, a class of cationic arginine-rich AMPs, are small peptides secreted by immune cells and epithelial cells that exert antimicrobial activity against a broad spectrum of microorganisms, including Gram-positive and Gram-negative bacteria and fungi. During Hp infections, AMP expression is able to eradicate the bacteria, thereby preventing Hp infections in gastrointestinal tract. It is likely that gastric β-defensins expression is increased during Hp infection. The aim of this review is to focus on increased knowledge of the role of β-defensins in response to Hp infection. We also briefly discuss the potential use of AMPs, either alone or in combination with conventional antibiotics, for the treatment of Hp infection.

Synthesis, hydrolysis, and skin retention of amino acid esters of α-tocopherol

The aim of this work was to synthesize new pro-vitamins of alpha-tocopherol (VE) able to release another moiety such as an amino acid, in order to obtain a combined antioxidant and moisturizing effect upon topical application. The new derivatives were characterized and tested for sensitivity to chemical and enzymatic hydrolysis. Lipophilicity was estimated using Log capacity factor and skin retention was determined in vitro, using rabbit ear skin as barrier. Five molecules were synthesized using L-proline, L-serine, L-tyrosine, L-asparagine, and L-citrulline as amino acidic moiety. All pro-vitamins showed similar or lower lipophilicity than alpha-tocopheryl acetate (VEAc), taken as reference, and similar stability in aqueous solutions. All pro-vitamins showed to be sensitive to enzymatic hydrolysis. None of the pro-vitamins crossed the skin in significant amounts, whereas they accumulated into the skin, in both the dermis and the epidermis. They are more hydrophilic and more water-soluble than the currently used acetate.

Synthesis and antihypertensive action of new Imidazo[1,2-a]pyridine derivatives, non peptidic Angiotensin II receptor antagonists

The synthesis and antihypertensive activity of a group of imidazo[1,2-a]pyridine is described. New synthesized compound have been tested both in vivo and in vitro as antagonists on Angiotensin AT1 receptor, and compared to Losartan, used as reference drug. Binding assay an Angiotensin AT1 receptor were carried on as well. Compounds 6b and 6g showed a potent antihypertensive activity and an high affinity on AT1 receptor.