ABSTRACT
A series of isoxazolyl, oxazolyl, and thiazolylpropionic acid derivatives derived from LDV was found to be a potent antagonist of the alpha(4)beta(1) integrin. The synthesis and SAR leading up to 3-[3-(1-[-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino]-3-methyl-butyl)-isoxazol-5-yl]-propionic acid (22) are reported. In an allergic mouse model, compound 22 was efficacious delivered systemically (58% inhib @ 10 mg/kg, sc) as well as by intra-tracheal instillation (ED(50)=2 microg/kg).
Subject(s)
Integrins/antagonists & inhibitors , Isoxazoles/pharmacology , Propionates/pharmacology , Receptors, Lymphocyte Homing/antagonists & inhibitors , Animals , Disease Models, Animal , Humans , Hypersensitivity/drug therapy , Integrin alpha4beta1 , Jurkat Cells , Mice , Structure-Activity RelationshipABSTRACT
High-throughput file screening against inhibition of human lung PDE4 led to the discovery of 3-ethyl-1-(4-fluorophenyl)-6-phenyl-7-oxo-4, 5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine (11) as a novel PDE4 inhibitor. Subsequent SAR development, using an eosinophil PDE assay, led to analogues up to 50-fold more potent than 11 with IC50 values of 0.03-1.6 microM. One such compound, CP-220,629 (22) (IC50 = 0.44 microM), was efficacious in the guinea pig aerosolized antigen induced airway obstruction assay (ED50 2.0 mg/kg, po) and demonstrated a significant reduction in eosinophil (55%), neutrophil (65%), and IL-1beta (82%) responses to antigen challenge in atopic monkeys (10 mg/kg, po).
Subject(s)
Anti-Asthmatic Agents , Anti-Inflammatory Agents, Non-Steroidal , Dihydropyridines , Eosinophils/enzymology , Isoenzymes/antagonists & inhibitors , Phosphodiesterase Inhibitors , Phosphoric Diester Hydrolases/metabolism , Pyrazoles , Airway Obstruction/immunology , Airway Obstruction/metabolism , Airway Obstruction/pathology , Airway Obstruction/prevention & control , Animals , Anti-Asthmatic Agents/chemical synthesis , Anti-Asthmatic Agents/chemistry , Anti-Asthmatic Agents/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Bronchoalveolar Lavage Fluid/cytology , Bronchoalveolar Lavage Fluid/immunology , Cell Count/drug effects , Cell Line , Cyclic AMP/metabolism , Cytokines/metabolism , Dihydropyridines/chemical synthesis , Dihydropyridines/chemistry , Dihydropyridines/pharmacology , Drug Evaluation, Preclinical , Eosinophils/drug effects , Eosinophils/immunology , Guinea Pigs , Humans , In Vitro Techniques , Macaca fascicularis , Molecular Conformation , Neutrophils/drug effects , Neutrophils/immunology , Ovalbumin/immunology , Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/chemistry , Phosphodiesterase Inhibitors/pharmacology , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyrrolidinones/pharmacology , Rolipram , Structure-Activity RelationshipABSTRACT
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).
