RESUMO
Transthyretin is a homotetrameric protein that carries thyroxine and retinol binding protein in plasma and is associated with a variety of amyloid diseases. One approach to the potential treatment of TTR amyloidosis is the stabilization of the native tetramer, over the dissociative transition state, through the binding of small molecules; this increases the kinetic barrier for tetramer dissociation and prevents protein misfolding. Several molecules discovered through focused screening, or created utilizing the structure-based design, were studied to identify the structural features that could make up for a good candidate drug. In this review, we examine several different chemical classes of TTR fibril formation inhibitors, highlighting the structural modifications that have led to an improvement or to a decrease of their potency and/or selectivity.
Assuntos
Amiloide/antagonistas & inibidores , Amiloide/química , Pré-Albumina/antagonistas & inibidores , Pré-Albumina/química , Amiloide/metabolismo , Humanos , Modelos Moleculares , Pré-Albumina/metabolismo , Ligação Proteica , Dobramento de Proteína , Relação Estrutura-AtividadeRESUMO
Some optically active 3-(arylmethylidene)aminoxy- (3a-g, 4a-g) and fluorenylideneaminoxy-2-methylpropionic acids (5, 6), were prepared as analogues of the antiinflammatory arylpropionic acids of type B, in which the aromatic group is substituted by an MAOM moiety. Some of the new compounds, tested in vivo for their antiinflammatory properties by means of the carrageenan-induced paw edema method in rats, exhibited activity indices similar to that shown in the same test by ibuprofen. Compounds 3a,b and 4a,b, for which at least one of the two enantiomers had shown an inhibition value higher than 40% in the in vivo test, were assayed for their in vitro enzymatic inhibitory activity, showing percentage inhibition values between 40 and 50% at a concentration of 10 microM against COX-2; at the same concentration, they appeared to be devoid of any activity towards COX-1. Compounds 3a,b and 4a,b also proved to possess a similar toxicity. The lack of enantioselectivity shown by compounds 3-6 was tentatively explained in terms of a conformational freedom of the enantiomers which allows their quasi-superimposition.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Propionatos/síntese química , Propionatos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Carragenina , Linhagem Celular , Ciclo-Oxigenase 2 , Modelos Animais de Doenças , Edema/induzido quimicamente , Edema/tratamento farmacológico , Feminino , Isoenzimas/antagonistas & inibidores , Macrófagos/efeitos dos fármacos , Macrófagos/enzimologia , Camundongos , Fenilpropionatos/síntese química , Fenilpropionatos/farmacologia , Fenilpropionatos/uso terapêutico , Prostaglandina-Endoperóxido Sintases , Ratos , Ratos Wistar , EstereoisomerismoRESUMO
New fluorescent ligands for adenosine receptors (ARs), obtained by the insertion, in the N(6) position of NECA, of NBD-moieties with linear alkyl spacers of increasing length, proved to possess a high affinity and selectivity for the A(3) subtype expressed in CHO cells. In fluorescence microscopy assays, compound 2d, the most active and selective for human A(3)-AR, permitted visualization and localization of this human receptor subtype, showing its potential suitability for internalization and trafficking studies in living cells.
Assuntos
Adenosina-5'-(N-etilcarboxamida)/química , Corantes Fluorescentes/química , Corantes Fluorescentes/metabolismo , Receptores Purinérgicos P1/metabolismo , Animais , Benzofuranos/química , Células CHO , Membrana Celular/metabolismo , Células Cultivadas , Cricetinae , Humanos , Ligantes , Microscopia de Fluorescência , Nitrocompostos/química , Receptor A2A de Adenosina , Receptor A3 de Adenosina , Receptores Purinérgicos P1/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismoRESUMO
Some 7-aminocephalosporanic acid (7-ACA) derivatives substituted on the C(7) nitrogen with 2-(arylmethyloxyimino)propionyl (3a-f), 2-(arylmethyloxyamino)propionyl (4a-d) and (arylmethyloxyamino)acetyl (2a-d) moieties were synthesized by reaction of the appropriate acylating agents with 7-ACA protected as a t-butyl ester, followed by removal of the t-butyl protecting group. The new compounds, tested in vitro for their antimicrobial activity against Gram-positive and Gram-negative bacteria, proved to possess a modest activity directed only against Gram-positive microorganisms.
Assuntos
Cefalosporinas/síntese química , Cefalosporinas/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade MicrobianaRESUMO
This paper reports the synthesis and aldose reductase (AR) inhibitory properties of some N-(benzyloxy) glycine derivatives (compounds 2-6), structurally related to the previously described N-(aroyl)-N-(arylmethyloxy) glycines A which had proved to possess an appreciable AR inhibitory activity. In compounds 2-5, spacers of different lengths and degrees of rigidity were inserted between the phenyl ring and the carbonyl group of type A derivatives; compound 6 differs from the most active type A derivative (compound 1) in the replacement of the methoxy moiety in the para position of the benzoyl side-chain with a group with different electronic characteristics, such as the trifluoromethyl moiety. Biological results indicated that among compounds 2-5 only derivative 3, which presents a CH2CH2 spacer between the phenyl and the carbonyl moiety, proved the possess AR inhibitory properties analogous to those of 1, while all the other compounds proved to be devoid of any significant activity. Furthermore, compound 6 showed an inhibitory activity about 3 times lower than that of 1.
Assuntos
Aldeído Redutase/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Glicina/farmacologia , Animais , Bovinos , Inibidores Enzimáticos/farmacologia , Glicina/análogos & derivados , Relação Estrutura-AtividadeRESUMO
The N-isopropyl- (3a-g) and N-tert-butyl-substituted (4a-g) (Z)-N-(3-(amino)-2-hydroxypropylidene)-(arylmethyloxy)amines were synthesized in order to compare their beta 1- and beta 2-adrenergic properties with those of their previously studied corresponding analogues with the E configuration (1a-g and 2a-g). Compounds 3 and 4 were tested for their affinity for beta 1-a and beta 2-adrenoceptors by radioligand binding experiments, and the compounds with the highest affinity were also assayed for their activity towards the same types of beta-adrenoceptors by functional tests on isolated preparations. The Z-methyloxyiminomethyl (Z-MOIM) compounds 3 and 4 proved to possess, on the whole, affinity (Ki) and activity (PIC50) indices similar to those of the E isomers 1 and 2, thus indicating that for the MOIM-type beta-adrenergic antagonists 1-4, the type of configuration around the MOIM double bond does not have any appreciable effect either on the affinity or on the activity towards beta-adrenoceptors. These results are rationalized on the basis of the steric and electronic analogies existing between the MOIM groups of 1-4 in the two types of configurations (E and Z).
Assuntos
Antagonistas Adrenérgicos beta/síntese química , Aminas/química , Aminas/síntese química , Receptores Adrenérgicos beta 1/fisiologia , Receptores Adrenérgicos beta 2/fisiologia , Antagonistas Adrenérgicos beta/química , Antagonistas Adrenérgicos beta/farmacologia , Aminas/farmacologia , Animais , Encéfalo/metabolismo , Bovinos , Desenho de Fármacos , Cobaias , Íleo , Técnicas In Vitro , Indicadores e Reagentes , Cinética , Pulmão/metabolismo , Masculino , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Ratos , Receptores Adrenérgicos beta 1/efeitos dos fármacos , Receptores Adrenérgicos beta 2/efeitos dos fármacos , Eletricidade Estática , Relação Estrutura-Atividade , TraqueiaRESUMO
A certain number of benzodihydrocarbazoles and benzotetrahydrocycloheptindoles were synthesized and tested for their antimicrobial activity. Compounds substituted on the nitrogen of the tetracyclic systems with a dimethylaminopropyl chain showed an antibacterial activity directed almost exclusively towards Gram-positive bacteria, while their N-unsubstituted analogs were completely inactive.
Assuntos
Antibacterianos/síntese química , Carbazóis/síntese química , Indóis/síntese química , Antibacterianos/farmacologia , Carbazóis/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Indóis/farmacologia , Testes de Sensibilidade Microbiana , Relação Estrutura-AtividadeRESUMO
In an attempt to change the beta-adrenergic properties of completely aliphatic 3-(methyleneaminoxy)propanolamine derivatives, from antagonist to agonist, while still retaining the beta 2-selectivity, we described, in a previous paper, the synthesis of a series of such derivatives possessing a hydroxy or methoxy group linked to the aliphatic substituent present on the oximic carbon. However, pharmacological tests indicated that these compounds maintain the competitive antagonism on beta receptors. In this paper, the synthesis and the results of functional tests on isolated preparations are reported for a new series of 3-(substituted-benzylideneaminoxy)propanolamine derivatives in which either the hydroxy or the methoxy group is linked to a phenyl ring present on the oximic carbon. The results obtained are then discussed, taking into account the conformational and reactivity properties of these compounds, determined by means of theoretical calculations.
Assuntos
Agonistas Adrenérgicos beta/síntese química , Compostos de Benzilideno/síntese química , Propanolaminas/síntese química , Agonistas de Receptores Adrenérgicos beta 1 , Agonistas de Receptores Adrenérgicos beta 2 , Agonistas Adrenérgicos beta/farmacologia , Animais , Compostos de Benzilideno/farmacologia , Cobaias , Técnicas In Vitro , Masculino , Conformação Molecular , Contração Muscular/efeitos dos fármacos , Propanolaminas/farmacologia , Espectrofotometria Infravermelho , Relação Estrutura-Atividade , Traqueia/efeitos dos fármacosRESUMO
Previous studies in the field of beta-adrenergic drugs had supported the hypothesis of the existence of a bioisosterism between the [(methyleneamino)oxy]methyl moiety (C = NOCH2, MAOMM) of type B beta-blocking drugs and the aryl (Ar) of type A beta-blocking agents. In the MAOMM, however, the carbon of the CH2 linked to the oximic oxygen possesses a hybridization (sp3) and a geometry different from those of the corresponding carbon of Ar which possesses an sp2 hybridization. Furthermore, in the MAOMM, in its preferred conformation, the unsaturated portion (C = N) is situated in a spatial area which does not correspond exactly to the area occupied by Ar. The formal inversion of the atomic sequence C = NOCH2 of the MAOMM leads to a different type of group, the [(methyloxy)imino]methyl moiety (CH2ON = C, MOIMM), which, in the E configuration, appears to present greater steric and electronic analogies with an Ar, with respect to the MAOMM. On the basis of these observations, some completely aliphatic (E)-N-(3-amino-2- hydroxypropylidene)(alkyloxy)amino derivatives of type C (11a,b and 12a, b) were synthesized, the their beta-adrenergic properties were compared with those of the corresponding [(methyleneamino)oxy]-methyl isomers of type B (19a, b and 20a, b). The similar beta-adrenergic properties of 11, 12 and 19, 20 evaluated in vitro both by radioligand binding assays and by functional tests on isolated preparations, are discussed on the basis of considerations regarding the spatial correspondences and electronic analogies between the MOIMM and the MAOMM.
Assuntos
Antagonistas Adrenérgicos beta/química , Iminas/farmacologia , Antagonistas de Receptores Adrenérgicos beta 1 , Antagonistas de Receptores Adrenérgicos beta 2 , Antagonistas Adrenérgicos beta/síntese química , Antagonistas Adrenérgicos beta/farmacologia , Animais , Bovinos , Etanolaminas/síntese química , Etanolaminas/química , Etanolaminas/farmacologia , Cobaias , Iminas/síntese química , Iminas/química , Técnicas In Vitro , Masculino , Conformação Molecular , Ensaio Radioligante , Ratos , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Relação Estrutura-AtividadeRESUMO
The 3-(methyleneaminoxy)methylmorpholines 2 were synthesized as analogues of viloxazine 1, an antidepressant drug, in which the aryloxymethyl group is substituted by a (methyleneaminoxy)methyl moiety (MAOMM). Compounds 2 were tested as potential antidepressant agents by using the test of antagonism to reserpine-induced hypothermy in mice. In addition, their anticholinergic and antihistaminic activity on isolated preparations and their ability to antagonize the toxicity induced by adrenaline in mice were evaluated. "In vivo" and "in vitro" tests showed that some compounds of type 2 possess a pharmacological profile similar to that of viloxazine 1.
Assuntos
Antidepressivos/síntese química , Morfolinas/síntese química , Animais , Antidepressivos/farmacologia , Temperatura Corporal/efeitos dos fármacos , Epinefrina/antagonistas & inibidores , Epinefrina/farmacologia , Epinefrina/toxicidade , Cobaias , Antagonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos/farmacologia , Imipramina/farmacologia , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos ICR , Morfolinas/farmacologia , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Parassimpatolíticos/farmacologia , Ratos , Ratos Wistar , Reserpina/antagonistas & inibidores , Reserpina/farmacologia , Viloxazina/farmacologiaRESUMO
Previous experimental and theoretical studies carried out on the mechanism of action of adrenergic drugs have shown that the (methyleneaminoxy)methyl moiety (C = NOCH2, MAOMM) can be considered as a "bioisostere" of an aryl group (Ar). On this basis, a series of substituted beta-aminoxypropionic acids (AOPAs) were synthesized as analogues of antiinflammatory arylacetic acids (ArAAs), in which the Ar portion is substituted by the MAOMM, with the aim of evaluating whether any antiinflammatory activity could be obtained from this class of drugs after the substitution of the Ar with the MAOMM. The antiinflammatory activity of the AOPAs synthesized was determined by carageenan-induced rat paw edema, using diclofenac as the reference drug. The pharmacological data showed that most of the AOPAs examined exhibit a significant antiinflammatory activity, which in the case of the (E)-3-(benzylideneaminoxy)propionic acid (7q) is very close to that of the reference drug. Structural and theoretical studies were carried out in order to compare the conformation and the molecular reactivity of the AOPAs with those of the ArAAs. Pharmacological results showed that the ArAAs also generally exhibit an antiinflammatory activity after the substitution of the Ar with the MAOMM, thus supporting the hypothesis of a bioisosterelike relationship between these two moieties in this class of NSAIDs.
Assuntos
Alanina/análogos & derivados , Anti-Inflamatórios não Esteroides/síntese química , Alanina/síntese química , Animais , Fenômenos Químicos , Química , Desenho de Fármacos , Feminino , Modelos Moleculares , Ratos , Ratos Endogâmicos , Relação Estrutura-AtividadeRESUMO
endo-3-Amino-exo-2-(3,4-dihydroxyphenyl)-2-hydroxybicyclo[2.2.1]he ptane (4a) and its N-isopropyl derivative (4b) were synthesized and assayed for their adrenergic activity on various isolated preparations. Compounds 4a and 4b, tested up to a dose of 10(-4) M, did not reveal any activity, either stimulant or blocking, on the alpha- and beta-adrenoceptors. Possible rationalizations of the results obtained, however, are suggested.
Assuntos
Compostos Bicíclicos com Pontes/farmacologia , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Catecolaminas/farmacologia , Receptores Adrenérgicos alfa/efeitos dos fármacos , Receptores Adrenérgicos beta/efeitos dos fármacos , Animais , Função Atrial , Compostos Bicíclicos com Pontes/síntese química , Catecolaminas/síntese química , Fenômenos Químicos , Química , Cobaias , Átrios do Coração/efeitos dos fármacos , Masculino , Conformação Molecular , Ratos , Ratos Endogâmicos , Receptores Adrenérgicos alfa/fisiologia , Receptores Adrenérgicos beta/fisiologia , Relação Estrutura-Atividade , Traqueia/efeitos dos fármacos , Traqueia/fisiologia , Ducto Deferente/efeitos dos fármacos , Ducto Deferente/fisiologiaRESUMO
We report unexpected results in an investigation of cyclic analogues of dopamine and norepinephrine possessing the structures 1-(aminomethyl)-5,6-dihydroxy-1,2,3,4-tetrahydronaphthalene (3) and 1-(aminomethyl)-5,6-dihydroxy-1,2,3,4-tetrahydro-1-naphthalenol (7). N-Isopropyl substitution of these compounds, providing 4 and 8, brings about the total disappearance of their stimulant activity on beta-adrenergic receptors. On the basis of current knowledge about the structure-activity relationship of adrenergic drugs, it is difficult to provide an explanation for these results; however a tentative rationalization based on conformational considerations is suggested.
Assuntos
Agonistas Adrenérgicos beta/síntese química , 1-Propanol , Agonistas Adrenérgicos beta/metabolismo , Agonistas Adrenérgicos beta/farmacologia , Animais , Desenho de Fármacos , Cobaias , Técnicas In Vitro , Indicadores e Reagentes , Masculino , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Ratos , Receptores Adrenérgicos beta/efeitos dos fármacos , Receptores Adrenérgicos beta/metabolismo , Relação Estrutura-AtividadeRESUMO
Two kinds of cyclic analogues of norepinephrine (NE, 7) and isoprenaline (ISO, 8), in which the C(1)-C(2) side chain of these amino alcohols is incorporated in its preferred conformation in the ring of the 2-(3,4-dihydroxyphenyl)-morpholines 9 and 10 (2-DPMs) and in the ring of the 3-(3,4-dihydroxyphenyl)-3-piperidinols 11 and 12 (3-DPPs), respectively, were synthesized and assayed for their adrenergic activity on various isolated preparations. The 2-DPMs and the 3-DPPs showed an alpha- and beta-agonist activity comparable to that of NE and ISO and to that of the trans-2-amino-5,6-dihydroxytetrahydronaphthalen-1-ols 13 and 14 (2-ADTNs), which represent another kind of semirigid analogue of NE and ISO. Through a comparison of the stereo structures of the compounds examined and of their pharmacological properties, it was possible to suggest a spatial situation in which the pharmacophoric groups of the adrenergic drugs examined (aryl moiety, amine nitrogen, and alcoholic or ethereal benzylic oxygen) should interact at the receptor site. This spatial situation corresponds to the one found in the preferred conformation of NE and ISO. It was also possible to construct two theoretical three-dimensional molecular models that provide information about steric requirements for the direct activation of alpha- and beta-adrenoceptors, respectively.