Synthesis and pharmacological evaluation of new compounds with a potential action on the adrenergic system.
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A series of compounds with a potential activity on both alpha and beta-adrenoreceptors were synthesized and evaluated with in vitro and in vivo tests. Aryloxypropanolamino derivatives N-substituted with alpha 2-benzodioxanylmethyl group showed a favourable alpha/beta ratio and a high selectivity towards beta 1 receptors. Substitution with different aralkyl groups afforded compounds with a low alpha-activity, although with a high potency and selectivity towards beta 1 receptors. The results are discussed on the basis of the working hypothesis and compared with those obtained for reference compounds.Keywords:
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A series of compounds with a potential activity on both alpha and beta-adrenoreceptors were synthesized and evaluated with in vitro and in vivo tests. Aryloxypropanolamino derivatives N-substituted with alpha 2-benzodioxanylmethyl group showed a favourable alpha/beta ratio and a high selectivity towards beta 1 receptors. Substitution with different aralkyl groups afforded compounds with a low alpha-activity, although with a high potency and selectivity towards beta 1 receptors. The results are discussed on the basis of the working hypothesis and compared with those obtained for reference compounds.
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In drug discovery, establishing a correlation between in vitro potency and in vivo activity is critical for the validation of the selected target and for developing confidence in the in vitro screening strategy. The present study developed a competition equilibrium dialysis assay using a 96-well dialysis technique to determine the intrinsic Kd for 13 inhibitors of human liver glycogen phosphorylase a (GPa) in the presence of liver homogenate to mimic the physiological environment. The results provided evidence that binding of an inhibitor to GPa was affected by extra cofactors present in the liver homogenate. A good correlation was demonstrated between the in vitro Kd determined under liver homogenate environment and free liver concentration of an inhibitor at the minimum efficacious dose in diabetic ob/ob mice. This study revealed important elements (such as endogenous cofactors missing from the in vitro assay and free concentration at the target tissue) that contributed to a better understanding of the linkage between in vitro and in vivo activity. The approach developed here may be applied to many drugs in pharmacology studies in which the correlation between in vitro and in vivo activities for the target tissue (such as solid tumors, brain, and liver) is critical.
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To evaluate the relationship between the in vitro and in vivo potency of sodium-glucose cotransporter (SGLT) inhibitors, a pharmacokinetic and pharmacodynamic (PK-PD) study was performed using normal rats. A highly selective SGLT2 inhibitor, tofogliflozin, and four other inhibitors with different in vitro inhibition potency to SGLT2 and selectivity toward SGLT2, versus SGLT1 were used as test compounds, and the time courses for urinary glucose excretion (UGE) and the plasma glucose and compound concentrations were monitored after administration of the compounds. A PK-PD analysis of the UGE caused by SGLT inhibition was performed on the basis of a nonlinear parallel tube model that took into consideration the consecutive reabsorption by different glucose transport properties of SGLT2 and SGLT1. The model adequately captured the time course of cumulative UGE caused by SGLT inhibition; then, the in vivo inhibition constants (Ki) of inhibitors for both SGLT1 and SGLT2 were estimated. The in vivo selectivity toward SGLT2 showed a good correlation with the in vitro data (r = 0.985; P < 0.05), with in vivo Ki values for SGLT2 in the range of 0.3–3.4-fold the in vitro data. This suggests that in vitro inhibition potency to both SGLT2 and SGLT1 is reflected in vivo. Furthermore, the complementary role of SGLT1 to SGLT2 and how selectivity toward SGLT2 affects the inhibitory potency for renal glucose reabsorption were discussed using the PK-PD model.
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The potency of 5 toxins of different microbial species has been studied by common in vivo methods and by the in vitro method based on measuring the relative test-microbe growth inhibiting units 50. The possibility of using this method for the determination of toxicity in vitro with a view of studying the potency of diphtheria and gas-gangrene exotoxins, as well as that of Pseudomonas aeruginosa exotoxin, is substantiated.
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In drug discovery or preclinical stages of development, potency parameters such as IC50, Ki, or Kd in vitro have been routinely used to predict the parameters of efficacious exposure (AUC, Cmin, etc.) in humans. However, to our knowledge, the fundamental assumption that the potency in vitro is correlated with the efficacious concentration in vivo in humans has not been investigated extensively. Thus, the present review examined this assumption by comparing a wide range of published pharmacokinetic (PK) and potency data. If the drug potency in vitro and its in vivo effectiveness in humans are well correlated, the steady-state average unbound concentrations in humans [Cu_ss.avg = fu·F·Dose/(CL·τ) = fu·AUCss/τ] after treatment with approved dosage regimens should be higher than, or at least comparable to, the potency parameters assessed in vitro. We reviewed the ratios of Cu_ss.avg/potency in vitro for a total of 54 drug entities (13 major therapeutic classes) using the dosage, PK, and in vitro potency reported in the published literature. For 54 drugs, the Cu_ss.avg/in vitro potency ratios were < 1 for 38 (69%) and < 0.1 for 22 (34%) drugs. When the ratios were plotted against fu (unbound fraction), "ratio < 1" was predominant for drugs with high protein binding (90% of drugs with fu ≤ 5%; i.e., 28 of 31 drugs). Thus, predicting the in vivo efficacious unbound concentrations in humans using only in vitro potency data and fu should be avoided, especially for molecules with high protein binding.
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Optimization of a previously disclosed sorbitol dehydrogenase inhibitor (SDI, II) for potency and duration of action was achieved by replacing the metabolically labile N,N‐dimethylsulfamoyl group with a variety of heterocycles. Specifically, this effort led to a series of novel, in vitro potent SDIs with longer serum half‐lives and acceptable in vivo activity in acutely diabetic rats (e.g., 62, 67, and 69). However, the desired in vivo potency in chronically diabetic rats, ED90 less than or equal to 5 mg/kg/day, was achieved only through further modification of the piperazine linker. Several members of this family, including 86, showed better than the targeted potency with ED90 values of 1‐2 mg/kg/day. Compound 86 was further profiled and found to be a selective inhibitor of sorbitol dehydrogenase, with excellent pharmacodynamic/pharmacokinetic properties, demonstrating normalization of sciatic nerve fructose in a chronically diabetic rat model for approximately 17 h, when administered orally at a single dose of 2 mg/kg/day.
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