A number of ethyl 4-(2-benzylalkyloxy)benzoates were prepared and their activity to induce precocious metamorphosis was evaluated in larvae of the silkworm, Bombyx mori, which was clearly recognized as a juvenile hormone (JH)-deficiency symptom. Ethyl 4-(2-benzylhexyloxy)benzoate (6) and its 2-benzylheptyloxy analog (7) were found to induce precocious metamorphosis at relatively low doses. Both enantiomers of 6 and 7 were prepared using a chiral auxiliary oxazolidinone. (S)-Enatiomers were more active than (R)-isomers at low doses of 0.1 and 1 mg, but at higher doses their activity was reversed. The activity of compound 6 could be fully counteracted by methoprene, a JH agonist, but not by the dietary administration of 20-hydroxyecdysone. The ester group was important in the ability to induce precocious metamorphosis. The (S)-enatiomer of 6 prolonged the duration of the instar and delayed the onset of cocoon spinning when applied to 5th instar larvae, suggesting that this compound might have JH-like activity as well as anti-JH activity.

A series of ethyl 4-[2-(6-methyl-3-pyridyloxy)alkyloxy]benzoates was prepared and tested for activity to induce precocious metamorphosis in larvae of the silkworm, Bombyx mori. Of the compounds tested, ethyl 4-[4-methyl-2-(6-methyl-3-pyridyloxy)pentyloxy]benzoate (5) was the most effective when applied to 24 hr-old 3rd instar larvae. There was no significant difference in precocious metamorphosis-inducing activity between 5R(ϩ)-and 5S(Ϫ)-enatiomers. The activity of compound 5 could be fully counteracted by methoprene, a juvenile hormone (JH) agonist, but not by the dietary administration of 20-hydroxyecdysone. When 3rd instar larvae were treated with compound 5, hemolymph JH esterase activity, which is indispensable for the initiation of pupation in normal last instar larvae, was induced during the 4th instar.

Novel indazole derivatives were prepared and evaluated for their biological activity and cardiovascular safety profile as human β3-adrenergic receptor (AR) agonists. Although the initial hit compound 5 exhibited significant β3-AR agonistic activity (EC50 = 21 nM), it also exhibited agonistic activity at the α1A-AR (EC50 = 219 nM, selectivity: α1A/β3 = 10-fold). The major metabolite of 5, which was an oxidative product at the indazole 3-methyl moiety, gave a clue to a strategy for improvement of the selectivity for β3-AR agonistic activity versus α1A-AR agonistic activity. Thus, modification of the 3-substituent of the indazole moiety effectively improved the selectivity to develop compound 11 with potent β3-AR agonistic activity (EC50 = 13 nM) and high selectivity (α1A/β3 = >769-fold). Compound 11 was also inactive toward β1 and β2-ARs and showed dose dependent β3-AR mediated relaxation of marmoset urinary bladder smooth muscle, while it did not obviously affect heart rate or blood pressure (iv, 3 mg/kg) in anesthetized rats.

A series of ethyl 4-(2-aryloxyhexyloxy)benzoates was prepared and tested for their activity to induce precocious metamorphosis in larvae of the silkworm. Phenyl analog 5 showed activity comparable to that of the 6-methyl-3-pyridyl analog reported as a novel anti-JH agent. The activity of 5 could be fully counteracted by methoprene, a JH agonist. The ethoxycarbonyl group of 5 was essential for its activity.Key words: anti-juvenile hormone; precocious metamorphosis; silkwormThe juvenile hormone (JH) is involved in a wide range of physiological processes in both developing and mature insects. 1) JH is critical for the regulation of metamorphosis and is required in the adult for such reproductive functions as pheromone biosynthesis, ovarian development, and maturation of eggs in females. Therefore, an anti-JH agent, which chemically blocks the functioning of the JH control system, could be an effective tool for studies on insect physiology as well as a potential insect growth regulator (IGR).2) Although some anti-JH agents have so far been found, including precocenes, fluoromevalonate, ethyl 4-[2-(tert-butylcarbonyloxy)butyloxy]benzoate (ETB) and 1,5-disubstituted imidazoles, their degree of activity is not sufficiently high for use as IGRs. 2)ETB is known to show both JH activity and anti-JH activity toward the tobacco hornworm, Manduca sexta, 3) and the silkworm, Bombyx mori, 4) depending on the dose applied: a low dose of ETB induced precocious metamorphosis, a clear sign of JH-deficiency, but at higher doses, the precocious metamorphosis-inducing activity disappeared and instead, JH-like activity was observed. Riddiford et al. have reported that ETB acted as a partial JH antagonist in the target tissue of the larval epidermis.5) By modifying the structure of ETB, we have recently found that ethyl 4-[2-(6-methyl-3-pyridyloxy)butyloxy]benzoate (1) induced precocious metamorphosis in 3rd instar larvae of B. mori at higher doses. 6) We have further synthesized analogs in which the ethyl side chain of 1 was modified, and found that butyl-substituted analog 2 was more potent than 1.7) In contrast to ETB, the activity of compounds 1 and 2 to induce precocious metamorphosis was correlated with the applied dose to some extent. In our continuing studies on this series of compounds, the butyl side chain was fixed in the molecule, and a modification was made by replacing the 6-methyl-3-pyridyl moiety with other aromatic rings. In the present paper, we report the activity of a novel series of ethyl 4-(2-aryloxyhexyloxy)benzoates as anti-JH agents causing precocious metamorphosis in B. mori larvae.Ethyl 4-(2-aryloxyhexyloxy)benzoates were prepared in a similar manner to that reported previously. 7) All compounds showed a single spot by thin-layer chromatography and an appropriate 1 H-NMR spectrum. B. mori (Shunrei  Shougetsu strain) larvae were reared on an artificial diet as previously reported. 8) Test compounds in an acetone solution (1-4 ml/larva) were topically applied to the dorsal abdomen of 24-hr-old 3rd instar and n...

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