Pharmacology of N-(3,5-Dichloro-1-oxido-4-pyridinyl)-8- methoxy-2-(trifluoromethyl)-5-quinoline Carboxamide (SCH 351591), a Novel, Orally Active Phosphodiesterase 4 Inhibitor M. MOTASIM BILLAH, NICOLA COOPER, MICHAEL MINNICOZZI, JULIE WARNECK, PENG WANG, JOHN A. HEY, WILLIAM KREUTNER, CHARLES A. RIZZO, SIDNEY R. SMITH, SIMON YOUNG, RICHARD W. CHAPMAN, HAZEL DYKE, NANG-YANG SHIH, JOHN J. PIWINSKI, FRANCIS M. CUSS, JOHN MONTANA, ASHIT K. GANGULY, and ROBERT W. EGAN Schering-Plough Research Institute, Kenilworth, New Jersey (M.M.B., M.M., P.W., J.A.H., W.K., C.A.R., S.R.S., S.Y., R.W.C., N.Y.S., J.J.P., F.M.C., A.K.G., R.W.E.); and Celltech Chiroscience Ltd., Cambridge, United Kingdom (N.C., J.W., H.D., J.M.) Received December 14, 2001; accepted March 19, 2002 This article is available online at http://jpet.aspetjournals.org ABSTRACT N-(3,5-Dichloro-1-oxido-4-pyridinyl)-8-methoxy-2-(trifluoro- methyl)-5-quinoline carboxamide (SCH 351591) has been iden- tified as a potent (IC 50  58 nM) and highly selective type 4 phosphodiesterase (PDE4) inhibitor with oral bioactivity in sev- eral animal models of lung inflammation. N-(3,5-Dichloro-4- pyridinyl)-8-methoxy-2-(trifluoromethyl)-5-quinoline carboxam- ide (SCH 365351), the only significant in vivo metabolite, is also a potent and highly selective PDE4 inhibitor (IC 50  20 nM). Both SCH 351591 and SCH 365351 inhibited cytokine produc- tion in human blood mononuclear cell preparations. Oral SCH 351591 significantly attenuated allergen-induced eosino- philia and airway hyperreactivity in allergic guinea pigs at doses as low as 1 mg/kg. In this model, oral SCH 365351 showed similar potency. When SCH 351591 was administered orally to allergic cynomolgus monkeys at 3 mg/kg, Ascaris suum- induced lung eosinophilia was blocked. Hyperventilation- induced bronchospasm in nonallergic guinea pigs, a model for exercise-induced asthma, was also suppressed significantly by oral SCH 351591 at 0.3 mg/kg. Cilomilast (SB 207499; Ariflo), a PDE4 inhibitor currently being developed for asthma and chronic obstructive pulmonary disease (COPD), was 10- to 30-fold less potent than SCH 351591 at inhibiting guinea pig lung eosinophilia and hyperventilation-induced bronchospasm. In a ferret model of emesis, maximum nonemetic oral doses of SCH 351591 and cilomilast were 5 and 1 mg/kg, respectively. Comparison of plasma levels at these nonemetic doses in ferrets to those at doses inhibiting hyperventilation-induced bronchospasm in guinea pigs gave a therapeutic ratio of 16 for SCH 351591 and 4 for cilomilast. Thus, SCH 351591 exhibits a promising preclinical profile as a treatment for asthma and COPD. Asthma is a complex multifactorial disease character- ized by reversible airway obstruction, airway inflamma- tion, and nonspecific airway hyperreactivity (Mayer and Wills-Karp, 1999; Bertrand, 2000). Chronic obstructive pulmonary diseases (COPDs), on the other hand, are char- acterized by mostly irreversible airway obstruction due to chronic bronchitis and emphysema (Hay, 2000). Inflamma- tion of the airways is believed to be central to the airways dysfunction in asthma and COPD (O’Shaughnessy et al., 1997; Roche, 1998). In these conditions, the airway wall is infiltrated by a variety of inflammatory cells, including mast cells, macrophages, T lymphocytes, eosinophils, and neutrophils. These cells release a host of mediators, in- cluding cytokines, chemokines, and bronchospastic agents that act in concert with neurotransmitters such as acetyl- choline and neurokinins from pulmonary nerves to produce bronchospasm, pulmonary edema, mucus hypersecretion, and other features of asthma and COPD. Eosinophilia is the dominant feature of lung inflammation in asthma, whereas COPD is marked by an intense pulmonary neu- trophilia. Although bronchodilators such as -agonists and anticholinergics are widely used for symptomatic relief, ABBREVIATIONS: COPD, chronic obstructive pulmonary disease; PDE, cyclic nucleotide phosphodiesterase; SPA, scintillation proximity assay; DMSO, dimethyl sulfoxide; TNF, tumor necrosis factor-; PBMC, peripheral blood mononuclear cell; LPS, lipopolysaccharide; ELISA, enzyme- linked immunosorbent assay; IL, interleukin; PIP, pulmonary insufflation pressure; PD, provocative dose; BAL, bronchoalveolar lavage; MED, minimum effective dose; HIB, hyperventilation-induced bronchospasm; AUC, area under the curve; SCH 351591, N-(3,5-dichloro-1-oxido-4- pyridinyl)-8-methoxy-2-(trifluoromethyl)-5-quinoline carboxamide; SCH 365351, N-(3,5-dichloro-4-pyridinyl)-8-methoxy-2-(trifluoromethyl)-5- quinoline carboxamide. 0022-3565/02/3021-127–137$7.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 302, No. 1 Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics 4847/990836 JPET 302:127–137, 2002 Printed in U.S.A. 127 at ASPET Journals on November 4, 2017 jpet.aspetjournals.org Downloaded from