Airway hyperresponsiveness (AHR), goblet cell metaplasia, and mucus overproduction are important features of bronchial asthma. To elucidate the molecular mechanisms behind these pulmonary pathologies, we examined for genes preferentially expressed in the lungs of a murine model of allergic asthma by using suppression subtractive hybridization (SSH). We identified a gene called gob-5 that had a selective expression pattern in the airway epithelium with AHR. Here, we show that gob-5, a member of the calcium-activated chloride channel family, is a key molecule in the induction of murine asthma. Intratracheal administration of adenovirus-expressing antisense gob-5 RNA into AHR-model mice efficiently suppressed the asthma phenotype, including AHR and mucus overproduction. In contrast, overexpression of gob-5 in airway epithelia by using an adenoviral vector exacerbated the asthma phenotype. Introduction of either gob-5 or hCLCA1, the human counterpart of gob-5, into the human mucoepidermoid cell line NCI-H292 induced mucus production as well as MUC5AC expression. Our results indicated that gob-5 may play a critical role in murine asthma, and its human counterpart hCLCA1 is therefore a potential target for asthma therapy.

A series of 4-phenylisoquinolone derivatives were synthesized and evaluated for NK1 (substance P) antagonist activity. Highly potent antagonists, 4-phenyl-3-isoquinolone-N-benzylcarboxamides (11), were discovered from the structure-activity relationship studies on the isoquinolone-urea lead 1a. Optimization of the activity in this series resulted in the development of 5-phenyl-6-pyrido[3,4-b]pyridine-N-benzylcarboxamides (30) which are highly potent orally active NK1 antagonists. Among the compounds synthesized, N-[3,5-bis(trifluoromethyl)benzyl]-7,8-dihydro-N,7-dimethyl-8-oxo-5- (substituted phenyl)-6-pyrido[3,4-b]pyridinecarboxamides (30a,f,g) showed excellent antagonist activities with IC50 values (in vitro inhibition of [125I]-BH-SP binding in human IM-9 cells) of 0.21-0.34 nM and ED50 values (in vivo inhibition of capsaicin-induced plasma extravasation in guinea-pig trachea, iv) of 0.017-0.030 mg/kg. These compounds exhibited significantly potent activity upon oral administration with ED50 values of 0.068-0.17 mg/kg. Conformational studies on 30g indicated that the two stable conformers of 30g are quite similar to those of CP-99,994.

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