Pharmacology ofN-(3,5-Dichloro-1-oxido-4-pyridinyl)-8-methoxy-2-(trifluoromethyl)-5-quinoline Carboxamide (SCH 351591), a Novel, Orally Active Phosphodiesterase 4 Inhibitor

Abstract

-5-quinoline carboxamide (SCH 351591) has been identified as a potent (IC 50 ϭ 58 nM) and highly selective type 4 phosphodiesterase (PDE4) inhibitor with oral bioactivity in several animal models of lung inflammation. N-(3,5-Dichloro-4-pyridinyl)-8-methoxy-2-(trifluoromethyl)-5-quinoline carboxamide (SCH 365351), the only significant in vivo metabolite, is also a potent and highly selective PDE4 inhibitor (IC 50 ϭ 20 nM). Both SCH 351591 and SCH 365351 inhibited cytokine production in human blood mononuclear cell preparations. Oral SCH 351591 significantly attenuated allergen-induced eosinophilia 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 suuminduced lung eosinophilia was blocked. Hyperventilationinduced 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.

Phosphodiesterase Type 4 Inhibitors Cause Proinflammatory Effects in Vivo

“…In mice (Corbel et al, 2002), treatment with piclamilast (assessed from 1 to 30 mg/kg) or NVP-ABE171 (Trifilieff et al, 2002) reduced BAL neutrophil numbers. Meanwhile in rats, inhibition of BAL neutrophilia was observed using cilomilast, SCH 351591, NVP-ABE171, rolipram, and AWD 12-281 (Escofier et al, 1999;Spond et al, 2001;Billah et al, 2002;Trifilieff et al, 2002;Kuss et al, 2003). The effect on BAL neutrophils observed here seems to be associated with a dose-dependent inhibition of BAL TNF-␣ levels.…”

“…Several PDE 4 inhibitors have also been demonstrated to be effective in rat models. Studies have shown inhibition of neutrophil numbers (Spond et al, 2001;Billah et al, 2002;Trifilieff et al, 2002;Kuss et al, 2003) and neutrophil activation in BAL (Trifilieff et al, 2002). In guinea pigs, rolipram treatment was shown to completely reverse the bronchoconstriction produced by chronic treatment with LPS (Toward and Broadley, 2002).…”

Exploring New Frontiers in Asthma Management for Optimal and Economic Outcomes

“…9 In animal studies, the second-generation PDE4 inhibitor cilomilast (also known as SB-207499) attenuated allergen-induced eosinophilia and airway hyperreactivity. 28 The drug also prevented bronchospasm in an animal model of exercise-induced asthma. 28 In humans with asthma, improvements in lung function were observed in clinical trials of oral cilomilast.…”

“…28 The drug also prevented bronchospasm in an animal model of exercise-induced asthma. 28 In humans with asthma, improvements in lung function were observed in clinical trials of oral cilomilast. 29 The drug was well tolerated and did not interact with albuterol or corticosteroids.…”

Cloning and Pharmacological Characterization of CXCR1 and CXCR2 fromMacaca fascicularis

“…Although homologs for CXCR1 and CXCR2 have been described for a variety on nonhuman species ( Figs. 1 and 2), we wanted to model CXCR1-and CXCR2-mediated responses in cynomolgus monkey (Macaca fascicularis), a species where diseases with a neutrophil component like chronic obstructive pulmonary disease, acute lung injury, and rheumatoid arthritis can be studied (Rose et al, 1992;Mihara et al, 2001;Billah et al, 2002). Thus, we cloned the genes encoding CXCR1 and CXCR2 from cynomolgus monkey, analyzed the pharmacological characteristics of these receptors, and identified them as functional homologs of hCXCR1 and hCXCR2.…”