A series of 1-aryl-2,3-bis(hydroxymethyl)naphthalene lignans have been synthesized and evaluated for their ability to selectively inhibit PDE IV isolated from guinea pig. Replacement of the 1-phenyl ring by a pyridone ring led to marked improvement of their selectivity for PDE IV over PDE III. The compounds that were most potent and selective involved those bearing an N-alkylpyridone ring at C-1. These compounds also showed potent antispasmogenic activity without causing significant changes in heart rate in the guinea pig. The most potent compound was 6,7-diethoxy-2,3-bis(hydroxymethyl)-1-[1-(2-methoxyethyl)-2-oxo-pyrid-4-yl]naphthalene (17f), ED50 values of histamine-induced and antigen-induced bronchoconstriction in the guinea pig being 0.08 and 2.3 mg/kg iv, respectively. This compound was chosen as a candidate for further pharmacological evaluation.
ABSTRACT-Tracheal relaxing effects and /32-selectivity of TA-2005 were investi gated by functional experiments and radioligand binding assay in guinea pigs in com parison with those of other ,Q-agonists, isoproterenol, procaterol, formoterol and sal butamol. The relaxing activity of TA-2005 on histamine-induced contraction in the isolated trachea was most potent among the five agonists, and it was blocked by a 82 selective antagonist (ICI 118,551) but not by a /3,-selective antagonist (bisoprolol). The potency of the relaxing effect was in the order of TA-2005 (pD-, = 9.79) > for moterol > procaterol > isoproterenol > salbutamol. The positive chronotropic effect of TA-2005 was similar to that of isoproterenol; and it was more potent than those of formoterol, procaterol and salbutamol in the isolated atria. The selectivity for tracheal muscle to atria of these agonists were in the order of procaterol > formoterol > TA 2005 > salbutamol >> isoproterenol. A radioligand binding experiment using guinea pig lung and cardiac ventricle as ,82 and 81-adrenoceptor sources, respectively, has also demonstrated that TA-2005 possesses extremely high affinity (IC50 = 1.04 nM) and selectivity (38-fold) to X32-adrenoceptors. By addition of GTP, the competition curve of [1251 ]iodocyanopindolol shifted rightward, indicating the agonist property. These results confirmed that TA-2005 is a highly 82-selective agonist that exerts a po tent tracheal relaxing effect.
1 The antihyperglycaemic e ect and the possible mechanism of action of T-174, a novel thiazolidinedione derivative, was determined in vivo and in vitro. 2 Oral administration of T-174 markedly improved hyperglycaemia, hyperinsulinaemia, hyperlipidaemia, and glucose intolerance in genetically obese and diabetic yellow KK (KK-A y ) mice (0.2 ± 15.5 mg kg 71 day 71 , for 7 days) and Zucker fatty rats (1.4 ± 11.4 mg kg 71 day 71 , for 6 days). The ED 50 values for the glucose lowering action of T-174 and pioglitazone, another thiazolidinedione antidiabetic, were 1.8 and 29 mg kg 71 day 71 , respectively in KK-A y mice; T-174 was about 16 times more potent than pioglitazone. 3 The hypoglycaemic e ect of exogenous insulin in KK-A y mice was enhanced after the administration of T-174. A hyperinsulinaemic euglycaemic clamp study in Zucker fatty rats showed an amelioration of whole-body insulin resistance by the T-174 treatment. 4 Insulin-stimulated glucose metabolism was enhanced in adipocytes from KK-A y mice treated with T-174. The insulin receptor number of the adipocytes was increased without a change in the a nity of the receptor. 5 The hypomagnesaemia in KK-A y mice was completely restored by T-174. 6 In cultured L6 myotubes, glucose consumption and [ 3 H]-2-deoxy-glucose transport were enhanced by T-174 (EC 50 ; 6 and 4 mM, respectively). Combination of insulin with T-174 was additive to stimulate glucose disposal. 7 These results suggest that the antihyperglycaemic e ect of T-174 was mediated by enhanced insulin action. This was associated with amelioration of the hypomagnesaemia and T-174 directly increased basal and insulin-stimulated glucose utilization by cultured muscle cells.
The relationship between CD4(+) T cell-mediated airway eosinophilic inflammation and bronchial hyper-responsiveness (BHR) was investigated. Ovalbumin-reactive T(h)0 clones were adoptively transferred to unprimed BALB/c mice and then the mice were challenged by inhalation of the relevant antigen. Upon antigen provocation, infused T(h) clones infiltrated into the airways, followed by the accumulation and degranulation of eosinophils, goblet cell hyperplasia, edema and increase in bronchial responsiveness to acetylcholine. Transfer of several clones that differed in the levels of IL-5 production revealed that the magnitude of in vivo eosinophilia strongly correlated with the IL-5-producing capacity of the infused T(h) clones. Administration of anti-IL-5 mAb almost completely suppressed antigen-induced eosinophilic inflammation and BHR. Administration of anti-IL-4 mAb or anti-IFN-gamma mAb enhanced the eosinophilia and BHR, whereas anti-IL-2 mAb did not affect them. The number of accumulated eosinophils significantly correlated with the intensity of BHR. Our present results clearly demonstrated that CD4(+) T cells induced BHR as a result of eosinophilic inflammation. IL-5 totally regulated both responses.
The structural requirements for potent and selective PDE4 inhibition were revealed in a 1-pyridylnaphthalene series, and the best compound (3kg, T-2585.HCl) was chosen for further biological evaluation (PDE4 inhibition IC50 = 0.13 nM, selectivity PDE3/4 ratio = 14 000). Compound 3kg showed potent antispasmogenic activities (ED50 = 0.063 mg/kg for reduction of antigen-induced bronchoconstriction, intravenously; ED50 = 0.033 mg/kg for reduction of histamine-induced bronchoconstriction, intraduodenally) in guinea pigs with little cardiovascular effects. Furthermore, 3kg induced significantly weaker emetic effects than RP73401 after oral administration in ferrets and intravenous administration in dogs (3kg, none of 4 ferrets vomited at a dose of 10 mg/kg, po and none of 8 dogs vomited at a dose of 0.3 mg/kg, iv; RP73401, 4 of 8 ferrets vomited at a dose of 3 mg/kg, po and 6 of 8 dogs vomited at a dose of 0.3 mg/kg, iv); that is compatible with the lower affinity for the high-affinity rolipram binding site (3kg, 2.6 nM; RP73401, 0. 85 nM). This may imply that 3kg has an improved therapeutic ratio because of a broad margin between the Ki value of binding affinity and the IC50 value of PDE4 inhibition (ratio = 0.050).
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