Resumo dos 5 artigos mais relevantes do grupo

KÜMMERLE, ARTHUR E., SCHMITT, MARTINE, CARDOZO, SUZANA V. S., LUGNIER, CLAIRE, VILLA, PASCAL, LOPES, ALEXANDRA B., ROMEIRO, NELILMA C., JUSTINIANO, HÉLÈNE, MARTINS, MARCO A., FRAGA, CARLOS A. M., BOURGUIGNON, JEAN-JACQUES, BARREIRO, ELIEZER J. Design, Synthesis, and Pharmacological Evaluation of N-Acylhydrazones and Novel Conformationally Constrained Compounds as Selective and Potent Orally Active Phosphodiesterase-4 Inhibitors. Journal of Medicinal Chemistry, 55, 7525-7545, 2012, doi:// 10.1021/jm300514y

Abstract: Among a small series of tested N-acylhydrazones (NAHs), the compound 8a was selected as a selective submicromolar phosphodiesterase-4 (PDE4) inhibitor associated with anti-TNF-alpha properties measured both in vitro and in vivo. The recognition pattern of compound 8a was elucidated through molecular modeling studies based on the knowledge of the 3D-structure of zardaverine, a PDE4 inhibitor resembling the structure of 8a, cocrystallized with the PDE4. Based on further conformational analysis dealing with N-methyl-NAHs, a quinazoline derivative (19) was designed as a conformationally constrained NAH analogue and showed similar in vitro pharmacological profile, compared with 8a. In addition 19 was found active when tested orally in LPS-evoked airway hyperreactivity and fully confirmed the working hypothesis supporting this work.

LACERDA, R. B., DASILVA L. L., LIMA, C. K. F., MIGUEZ, E., MIRANDA, A. L. P., LAUFER, S., BARREIRO, ELIEZER J., FRAGA, CARLOS A. M. Discovery of novel orally active anti-inflammatory N-phenylpyrazolyl-N-glycinylhydrazone derivatives that Inhibit TNF-α production. Plos One, 7, e46925, 2012, doi:// 10.1371/journal.pone.0046925

Abstract: Herein, we describe the synthesis and pharmacological evaluation of novel N-phenylpyrazolyl-N-glycinyl-hydrazone derivatives that were designed as novel prototypes of p38 mitogen-activated protein kinase (MAPK) inhibitors. All of the novel synthesized compounds described in this study were evaluated for their in vitro capacity to inhibit tumor necrosis factor a (TNF-a production in cultured macrophages) and in vitro MAPK p38a inhibition. The two most active anti-TNF-alpha derivatives, (E)-2-(3-tert-butyl-1-phenyl-1H-pyrazol-5-ylamino)-N’-((4-(2-morpholinoethoxy)naphthalen-1-yl)methylene) acetohydrazide (4a) and (E)-2-(3-tert-butyl-1-phenyl-1H-pyrazol-5-ylamino)-N’-(4-chlorobenzylidene)acetohydrazide (4f), were evaluated to determine their in vivo anti-hyperalgesic profiles in carrageenan-induced thermal hypernociception model in rats. Both compounds showed anti-inflammatory and antinociceptive properties comparable to SB-203580 used as a standard drug, by oral route at a dose of 100 mmol/kg. This bioprofile is correlated with the ability of NAH derivatives (4a) and (4f) suppressing TNF-alpha levels in vivo by 57.3 and 55.8%, respectively.

BARREIRO, ELIEZER J., KUMMERLE, ARTHUR E., FRAGA, CARLOS A. M. The methylation effect in medicinal chemistry. Chemical Reviews, 111, p. 5215-5246, 2011, doi://10.1021/cr200060g

Abstract: The manuscript describes the importance of the methyl group in the biological performance of distinct bioactive compounds and several drugs, acting at diferent receptors types with various different therapeutic indications. As well the introduction of a methyl group instead a hydrogen atom, giving a homolog derivative, can produce deeply modifications in the biological behavior of the molecule in the pharmacodynamic or pharmacokinetic phases. From several examples the effect of the methyl group will be discussed herein. The authors not consider the functional group modification performed by a methyl introduction over a functional group e.g. an ester coming from an acid or a methyl ether coming from a phenol, and so on, as promoting the methyl effect treated in this manuscript.

LIMA, LIDIA M., CASTRO, P., MACHADO, A. L., FRAGA, CARLOS A. M., LUGNIER, C., MORAES, V. L. G., BARREIRO, ELIEZER J. Synthesis and anti-inflammatory activity of phthalimide derivatives, designed as new thalidomide analogues. Bioorganic and Medicinal Chemistry, v. 10, p. 3067-3073, 2002, doi://10.1016/S0968-0896(02)00152-9

Abstract: This paper describes the synthesis and anti-inflammatory activity of new N-phenyl-phthalimide sulfonamides (3a–e) and the isosters N-phenyl-phthalimide amides (4a–e), designed as hybrids of thalidomide (1) and aryl sulfonamide phosphodiesterase inhibitor (2). In these series, compound 3e (LASSBio-468), having a sulfonyl-thiomorpholine moiety, showed potent inhibitory activity on LPS-induced neutrophil recruitment with ED50=2.5 mg kg−1, which was correlated with its inhibitory effect on TNF-α level.

SERRATOS, H. G., CHANG, R., PEREIRA, E. F. R., CASTRO, N. G., ARACAVA, Y., MELO, P. A., LIMA, P. C., FRAGA, CARLOS A. M., BARREIRO, ELIEZER J., ALBUQUERQUE, E. X. A novel thienylhydrazone, 2-(thienylidene) 3,4-methylenedioxylbenzoylhydrazine, increases inotropism and descreases fatigue of skeletal muscle. Journal of Pharmacology and Experimental Therapeutics, 299, 558-566, 2001, http://jpet.aspetjournals.org/content/299/2/558.full.pdf+html

Abstract: This study was designed to investigate the effects on single skeletal muscle fibers of a novel thienylhydrazone, referred to as LASSBio-294, which is a bioisoster of pyridazinone compounds that inhibit the cyclic AMP-specific phosphodiesterase (PDE) 4. Twitch and fatigue were analyzed in single skeletal muscle fibers isolated from either the semitendinous or the tibialis anterior muscles dissected from the frogRana pipiens. LASSBio-294 (12.5–100 μM) increased twitch tension, accelerated the maximal rate of tension decay during relaxation, and had very little effect in the maximal rate of tension development of muscle fibers directly stimulated at ≤30 Hz. The positive inotropic effect of LASSBio-294 developed slowly, reaching its maximum at 40 min and was inversely proportional to the frequency of stimulation, becoming negligible at 60 and 90 Hz. The concentration-response relationship for LASSBio-294-induced potentiation of twitch tension was bell-shaped, with maximal effect occurring at 25 μM. In addition, LASSBio-294 reduced development of fatigue induced by tetanic stimulation of the muscle fibers and reduced the time needed for 80% prefatigue tension recovery after fatigue had developed to 50% of the maximal pretetanic force. These effects of LASSBio-294 can be fully explained by stimulation of the sarcoplasmic reticulum Ca2+ pump and could be ascribed to an increase in cellular levels of cyclic AMP due to PDE inhibition. The novel thienylhydrazone LASSBio-294 may be useful for treatment of patients suffering from conditions in which muscle fatigue is a debilitating symptom (e.g., chronic heart failure).