title: Biarylcarboxylic acids and -amides: inhibition of phosphodiesterase type IV versus [3H]rolipram binding activity and their relationship to emetic behavior in the ferret.
abstract: In addition to having desirable inhibitory effects on inflammation, anaphylaxis, and smooth muscle contraction, PDE-IV inhibitors also produce undesirable side effects including nausea and vomiting. In general, compounds that inhibit PDE-IV also potently displace [3H]rolipram from a high-affinity binding site in rat cortex. While this binding site has not been identified, it has been proposed to be an allosteric binding site on the PDE-IV enzyme. Preliminary studies have suggested that the emetic potency of PDE-IV inhibitors is correlated with affinity for the brain rolipram binding site rather than potency at inhibiting PDE-IV enzyme activity. Efforts to eliminate the emetic potential of PDE-IV inhibitors were directed toward developing compounds with decreased [3H]rolipram binding affinity while retaining PDE-IV potency. Thus, a novel series of 4-(3-alkoxy-4-methoxyphenyl)benzoic acids and their corresponding carboxamides were prepared and evaluated for their PDE-IV inhibitory and rolipram binding site properties. Modification of the catechol ether moiety led to phenylbutoxy and phenylpentoxy analogues that provided the desired activity profile. Specifically, 4-[3-(5-phenylpentoxy)-4-methoxyphenyl]-2-methylbenzoic acid, 18, was found to exhibit potent PDE-IV inhibitory activity (IC50 0.41 microM) and possessed 400 times weaker activity than rolipram for the [3H]rolipram binding site. In vivo, compound 18 was efficacious in the guinea pig aerosolized antigen induced airway obstruction assay (ED50 8.8 mg/kg, po) and demonstrated a significant reduction in emetic side effects (ferret, 20% emesis at 30 mg/kg, po).
authors.affiliation: Central Research Division, Pfizer Inc, Groton, Connecticut 06340, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Duplantier
authors.forename: M S
authors.initials: MS
authors.lastname: Biggers
authors.forename: R J
authors.initials: RJ
authors.lastname: Chambers
authors.forename: J B
authors.initials: JB
authors.lastname: Cheng
authors.forename: K
authors.initials: K
authors.lastname: Cooper
authors.forename: D B
authors.initials: DB
authors.lastname: Damon
authors.forename: J F
authors.initials: JF
authors.lastname: Eggler
authors.forename: K G
authors.initials: KG
authors.lastname: Kraus
authors.forename: A
authors.initials: A
authors.lastname: Marfat
authors.forename: H
authors.initials: H
authors.lastname: Masamune
authors.forename: J S
authors.initials: JS
authors.lastname: Pillar
authors.forename: J T
authors.initials: JT
authors.lastname: Shirley
authors.forename: J P
authors.initials: JP
authors.lastname: Umland
authors.forename: J W
authors.initials: JW
authors.lastname: Watson
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases; D000818:Animals; D001565:Benzoates / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D005289:Ferrets; D006168:Guinea Pigs; D006801:Humans; D051379:Mice; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D011760:Pyrrolidinones / Q000378:metabolism*; D020889:Rolipram; D013329:Structure-Activity Relationship; D014839:Vomiting / Q000139:chemically induced
chemical_list: C097772:4-(4-methoxy-3-(5-phenylpentoxy)phenyl)-2-methylbenzoic acid; D001565:Benzoates; D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; D010727:Phosphoric Diester Hydrolases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram