title: Novel class of benzoic acid ester derivatives as potent PDE4 inhibitors for inhaled administration in the treatment of respiratory diseases.
abstract: The first steps in the selection process of a new anti-inflammatory drug for the inhaled treatment of asthma and chronic obstructive pulmonary disease are herein described. A series of novel ester derivatives of 1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloropyridin-4-yl) ethanol have been synthesized and evaluated for inhibitory activity toward cAMP-specific phosphodiesterase-4 (PDE4). In particular, esters of variously substituted benzoic acids were extensively explored, and structural modification of the alcoholic and benzoic moieties were performed to maximize the inhibitory potency. Several compounds with high activity in cell-free and cell-based assays were obtained. Through the evaluation of opportune in vitro ADME properties, a potential candidate suitable for inhaled administration in respiratory diseases was identified and tested in an in vivo model of pulmonary inflammation, proving its efficacy.
authors.affiliation: Chiesi Farmaceutici S.p.A., Nuovo Centro Ricerche , Largo Belloli 11/a, 43122 Parma, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Armani
authors.forename: Gabriele
authors.initials: G
authors.lastname: Amari
authors.forename: Andrea
authors.initials: A
authors.lastname: Rizzi
authors.forename: Renato
authors.initials: R
authors.lastname: De Fanti
authors.forename: Eleonora
authors.initials: E
authors.lastname: Ghidini
authors.forename: Carmelida
authors.initials: C
authors.lastname: Capaldi
authors.forename: Laura
authors.initials: L
authors.lastname: Carzaniga
authors.forename: Paola
authors.initials: P
authors.lastname: Caruso
authors.forename: Matilde
authors.initials: M
authors.lastname: Guala
authors.forename: Ilaria
authors.initials: I
authors.lastname: Peretto
authors.forename: Elena
authors.initials: E
authors.lastname: La Porta
authors.forename: Pier T
authors.initials: PT
authors.lastname: Bolzoni
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Facchinetti
authors.forename: Chiara
authors.initials: C
authors.lastname: Carnini
authors.forename: Nadia
authors.initials: N
authors.lastname: Moretto
authors.forename: Riccardo
authors.initials: R
authors.lastname: Patacchini
authors.forename: Franco
authors.initials: F
authors.lastname: Bassani
authors.forename: Valentina
authors.initials: V
authors.lastname: Cenacchi
authors.forename: Roberta
authors.initials: R
authors.lastname: Volta
authors.forename: Francesco
authors.initials: F
authors.lastname: Amadei
authors.forename: Silvia
authors.initials: S
authors.lastname: Capacchi
authors.forename: Maurizio
authors.initials: M
authors.lastname: Delcanale
authors.forename: Paola
authors.initials: P
authors.lastname: Puccini
authors.forename: Silvia
authors.initials: S
authors.lastname: Catinella
authors.forename: Maurizio
authors.initials: M
authors.lastname: Civelli
authors.forename: Gino
authors.initials: G
authors.lastname: Villetti
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001249:Asthma / Q000188:drug therapy*; D001565:Benzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002908:Chronic Disease; D018360:Crystallography, X-Ray; D004802:Eosinophilia / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D004952:Esters; D006168:Guinea Pigs; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000201:enzymology; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008173:Lung Diseases, Obstructive / Q000188:drug therapy*; D062105:Molecular Docking Simulation; D010047:Ovalbumin; D058988:Phosphodiesterase 4 Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D062366:para-Aminobenzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C000596339:tanimilast; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001565:Benzoates; D004952:Esters; D058988:Phosphodiesterase 4 Inhibitors; D013449:Sulfonamides; D062366:para-Aminobenzoates; D010047:Ovalbumin