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.
N-(3,5-Dichloro-1-oxido-4-pyridinyl)-8-methoxy-2-(trifluoromethyl)-5-quinoline carboxamide (SCH 351591) has been identified as a potent (IC(50) = 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) = 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 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.
Billah
M Motasim
MM
Schering-Plough Research Institute, 2015 Galloping Hill Road, K15-1-1660 Kenilworth, NJ 07033, USA. motasim.billah@spcorp.com
Cooper
Nicola
N
Minnicozzi
Michael
M
Warneck
Julie
J
Wang
Peng
P
Hey
John A
JA
Kreutner
William
W
Rizzo
Charles A
CA
Smith
Sidney R
SR
Young
Simon
S
Chapman
Richard W
RW
Dyke
Hazel
H
Shih
Nang-Yang
NY
Piwinski
John J
JJ
Cuss
Francis M
FM
Montana
John
J
Ganguly
Ashit K
AK
Egan
Robert W
RW
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D016535:Bronchial Hyperreactivity / Q000517:prevention & control; D001986:Bronchial Spasm / Q000517:prevention & control; D001993:Bronchodilator Agents / Q000494:pharmacology; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004639:Emetics / Q000494:pharmacology; D005260:Female; D005289:Ferrets; D006168:Guinea Pigs; D006801:Humans; D006985:Hyperventilation / Q000503:physiopathology; D018664:Interleukin-12 / Q000096:biosynthesis; D015848:Interleukin-5 / Q000096:biosynthesis; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008875:Middle Aged; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D020889:Rolipram / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D018927:Anti-Asthmatic Agents; D001993:Bronchodilator Agents; D003497:Cyclic N-Oxides; D004639:Emetics; D015848:Interleukin-5; D010726:Phosphodiesterase Inhibitors; D011804:Quinolines; C459379:SCH 351591; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram