RESUMEN
PURPOSE: To examine the structure-activity relationships for the inhibition of the activity of recombinant human CYP3A4 and to establish a generalized, quantitative physicochemical model for use in early drug discovery. METHODS: Inhibition of the activity of recombinant human CYP3A4 (erythromycin N-demethylase) by 30 diverse chemicals was studied using enhanced throughput methodology. RESULTS: There was a general, strong correlation between the IC50 value determined against erythromycin N-demethylase activity and lipophilicity (LogD7.4) (r2 = 0.68, p <0.0001). This relationship was strengthened further by subdividing the structures studied into two distinct subpopulations of chemistry within the dataset. These could be identified by the absence (r2 = 0.80, p <0.0001) or presence (r2 = 0.69, p <0.0001) of a sterically uninhindered N-containing heterocycle, more specifically a pyridine, imidazole, of triazole function. The presence of these structural motifs increased the potency of CYP3A4 inhibition by approximately 10-fold for a given lipophilicity (LogD7.4.value). More detailed analyses of AstraZeneca compounds demonstrated that the inhibitory potency of the pyridine structure can be attenuated through direct steric effects or electronic substitution resulting in a modulation of the pKa of the pyridine nitrogen, thereby influencing its ability to interact with the CYP heme. CONCLUSIONS: A generalized, quantitative model is proposed for the inhibition of the major drug metabolizing enzyme, CYP3A4. This model indicates the importance of lipophilicity and rationalizes increased potency arising through additional interactions with the heme iron. These general relationships were shown to be applicable to a selection of compounds of interest to several early research projects.
Asunto(s)
Citocromo P-450 CYP1A1/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Algoritmos , Fenómenos Químicos , Química Física , Humanos , Indicadores y Reactivos , Modelos Químicos , Piridinas/química , Proteínas Recombinantes/químicaRESUMEN
The distribution of salmeterol and proxicromil between unilamellar vesicles of dioleoylphosphatidylcholine (DOPC) and aqueous buffer at pH 7.4 has been studied, using an ultrafiltration method, as a function of compound concentration, DOPC concentration, and buffer ionic strength. The binding of these ionized lipophilic compounds to neutral DOPC vesicles induces a surface charge, which causes the observed membrane distribution coefficient D(mem)obs to vary significantly with bound compound to DOPC ratio and with ionic strength. This variability is shown to be well-described with use of the Gouy-Chapman theory of the ionic double layer and is contrasted with the ideal behavior shown by the neutral compound clofibrate. Increasing ionic strength is also shown to increase the observed 1-octanol-buffer distribution coefficients D(o/w)obs of proxicromil but through a very different mechanism involving the extraction of ion pairs. This study highlights the experimental difficulty in determining concentration-independent liposome distribution coefficients of ionized lipophilic compounds and describes when deviations will be significant and how observed values may be corrected for such effects. The general effect of ionic strength on membrane-buffer distribution and 1-octanol-buffer distribution is discussed with particular reference to the very different propensity for ion pair formation shown by the two systems, and the most suitable experimental conditions that should be used with each system.
Asunto(s)
1-Butanol/química , Albuterol/análogos & derivados , Cromonas/química , Albuterol/química , Tampones (Química) , Clofibrato/química , Portadores de Fármacos , Concentración de Iones de Hidrógeno , Liposomas , Concentración Osmolar , Fosfatidilcolinas/química , Xinafoato de SalmeterolRESUMEN
The distribution of four ionizing molecules between small unilamellar vesicles of dimyristoylphosphatidylcholine (DMPC) and aqueous buffers has been studied as a function of pH using an ultrafiltration method. The results show that pH-distribution behavior observed in the standard 1-octanol-water system does not always apply in model membrane systems, since the charged form of some molecules are able to partition into a phospholipid bilayer. It was further shown that the partitioning of these charged species into the bilayer is not as a consequence of ion pairing. The results clarify reports suggesting that protonated amines have a surprisingly high membrane affinity, and the implications of these findings for drug design are discussed.
Asunto(s)
Dimiristoilfosfatidilcolina/química , Membranas Artificiales , Agua/química , Amlodipino/química , Amlodipino/farmacocinética , Tampones (Química) , Fenómenos Químicos , Química Física , Dimiristoilfosfatidilcolina/metabolismo , Iones , Cinética , Membrana Dobles de Lípidos/química , Membrana Dobles de Lípidos/metabolismo , Agua/metabolismoRESUMEN
Methyl 2,5-dimethyl-4-[2-(phenylmethyl)benzoyl]-1H-pyrrole-3-carboxylate, FPL 64176 (1), is the first example of a new class of calcium channel activator (CCA) that does not act on any of the well-defined calcium channel modulator receptor sites, as typified by verapamil, diltiazem, and the dihydropyridines. The potent activity of 1, having the 2-(phenylmethyl)benzoyl substituent, was predicted using QSAR on an initial set of less potent benzoylpyrroles. When compared to the CCA Bay K 8644, 1 has similar potency on calcium uptake into GH3 cells (both have EC50 approximately 0.015 microM) but is appreciably more potent functionally at increasing contractility in a guinea pig atria preparation (1 has EC50 = 0.049 microM vs Bay K 8644 EC50 = 1.95 microM). 1 is an achiral, pharmacologically clean agonist with no demonstrable partial agonist properties and possesses appreciably higher efficacy than Bay K 8644. It should therefore become a useful biochemical and pharmacological tool for the study of calcium channels in many cell types.
Asunto(s)
Agonistas de los Canales de Calcio/síntesis química , Pirroles/síntesis química , Ácido 3-piridinacarboxílico, 1,4-dihidro-2,6-dimetil-5-nitro-4-(2-(trifluorometil)fenil)-, Éster Metílico/farmacología , Animales , Agonistas de los Canales de Calcio/farmacología , Cobayas , Contracción Miocárdica/efectos de los fármacos , Pirroles/farmacología , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Two novel series of dihydrothiadiazole ring containing inhibitors of angiotensin converting enzyme have been designed and synthesized. The compounds are highly potent enzyme inhibitors and, as a consequence of conformational restriction, chemically stable with respect to undesirable cyclization reactions. The most interesting compound from this series, 5a (FPL 63547), is the monoethyl ester prodrug of the highly potent "aminocarboxy" inhibitor 5b (FPL 63674). It produces an antihypertensive effect of long duration in animal models after oral dosing. Unlike other ACE inhibitors, 5b is eliminated almost entirely by biliary clearance in the rat. The favorable pharmacological properties of 5a and 5b are rationalized in terms of their unique physicochemical profiles. The clear preference for biliary clearance seen with 5b is consistent with its lipophilicity and its high degree of net ionization at physiological pH, which results from the very low pKa of the C-terminus carboxylic acid function. FPL 63547 is presently undergoing clinical investigation in man.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/síntesis química , Antihipertensivos/síntesis química , Bilis/metabolismo , Tiadiazoles/síntesis química , Animales , Diseño de Fármacos , Indicadores y Reactivos , Masculino , Tasa de Depuración Metabólica , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Ratas , Relación Estructura-Actividad , Tiadiazoles/química , Tiadiazoles/metabolismo , Tiadiazoles/farmacología , Difracción de Rayos XRESUMEN
1. Metabolism of basic drugs may result in the formation of zwitterionic sulphate conjugates. The additional ionization introduced by the sulphate group into these compounds compared with the basic parent drug does not produce a corresponding increase in hydrophilic character. 2. Zwitterionic conjugates have constant lipophilicity between their pKa values. The opposite charges on the ionizing functional groups in this pH range appear to cancel the effect of each other on lipophilicity. 3. In the case of propranolol the O-sulphate derivative is more lipophilic than the parent compound at pH values below 7, despite the ionized character of the sulphate function. 4. The decrease in lipophilicity appears to be related to the separation in the molecular structure of the amino and sulphate groups.
Asunto(s)
Piperazinas/metabolismo , Propranolol/análogos & derivados , Propranolol/metabolismo , Benzotiazoles , Fenómenos Químicos , Química Física , Cromatografía Líquida de Alta Presión , Concentración de Iones de Hidrógeno , Cinética , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Sulfatos/metabolismoRESUMEN
A new primate model has been developed for the evaluation of antiallergic agents. Compounds are tested for their ability to inhibit anti-IgE induced histamine release from the bronchoalveolar mast cells lavaged from the lungs of Macaca arctoides infected with the parasite Ascaris suum. A number of 6-substituted pyranoquinoline derivatives have been evaluated and the activities were subjected to Hansch analysis. A highly significant correlation with lipophilicity (pi) and Hammett sigma p values was obtained. The relationship was used to predict further compounds for synthesis giving rise to new, potent analogues. Some apparently anomalous results could be explained by differences in the ionization of, or tautomerism in, the quinoline ring.
Asunto(s)
Modelos Animales de Enfermedad , Hipersensibilidad/tratamiento farmacológico , Piranos/uso terapéutico , Quinolinas/uso terapéutico , Animales , Ascariasis/inmunología , Líquido del Lavado Bronquioalveolar/citología , Fenómenos Químicos , Química , Cromolin Sódico/uso terapéutico , Liberación de Histamina/efectos de los fármacos , Hipersensibilidad/inmunología , Inmunoglobulina E/inmunología , Macaca , Mastocitos/fisiología , Piranos/síntesis química , Piranos/farmacología , Quinolinas/síntesis química , Quinolinas/farmacología , Relación Estructura-ActividadRESUMEN
1. The consequences of metabolic transformation on lipophilicity have been considered using the terms log P (partition coefficient) and log D (distribution coefficient). 2. Transformations which result in no change in the degree of ionisation can be readily predicted by the use of fragmental constants and log P. 3. If metabolism alters the degree of ionization then the distribution coefficient, log D, at physiological pH is a more appropriate term to use. Intuitive empirical observations may be incorrect and lead to false assumptions about the lipophilicity or water solubility of metabolites. 4. Metabolism may form zwitterionic molecules. These metabolites need special consideration since their penetration into lipid phases may be greater than expected.
Asunto(s)
Farmacocinética , Biotransformación , Metabolismo de los Lípidos , Modelos BiológicosRESUMEN
Gastrointestinal absorption of the strongly acidic drug proxicromil has been studied with respect to its physical organic chemistry. The lipophilicity of the drug above pH 6 in octanol-buffer partition experiments is dependent on ion pair formation. Similar trends were demonstrated for the in vitro partition of the compound into GI tissue. The absorption of the compound from the perfused GI tract of rats in vivo was not consistent with classical un-ionized drug absorption theories and indicated the operation of other processes, especially ion pair formation, as major mechanisms of proxicromil absorption.