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CHF6001 I: a novel highly potent and selective phosphodiesterase 4 inhibitor with robust anti-inflammatory activity and suitable for topical pulmonary administration.
J Pharmacol Exp Ther 2015; 352(3):559-67JP

Abstract

This study examined the pharmacologic characterization of CHF6001 [(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-(cyclopropylmethoxy)-4-(methylsulfonamido)benzoyloxy)ethyl)pyridine 1-oxide], a novel phosphodiesterase (PDE)4 inhibitor designed for treating pulmonary inflammatory diseases via inhaled administration. CHF6001 was 7- and 923-fold more potent than roflumilast and cilomilast, respectively, in inhibiting PDE4 enzymatic activity (IC50 = 0.026 ± 0.006 nM). CHF6001 inhibited PDE4 isoforms A-D with equal potency, showed an elevated ratio of high-affinity rolipram binding site versus low-affinity rolipram binding site (i.e., >40) and displayed >20,000-fold selectivity versus PDE4 compared with a panel of PDEs. CHF6001 effectively inhibited (subnanomolar IC50 values) the release of tumor necrosis factor-α from human peripheral blood mononuclear cells, human acute monocytic leukemia cell line macrophages (THP-1), and rodent macrophages (RAW264.7 and NR8383). Moreover, CHF6001 potently inhibited the activation of oxidative burst in neutrophils and eosinophils, neutrophil chemotaxis, and the release of interferon-γ from CD4(+) T cells. In all these functional assays, CHF6001 was more potent than previously described PDE4 inhibitors, including roflumilast, UK-500,001 [2-(3,4-difluorophenoxy)-5-fluoro-N-((1S,4S)-4-(2-hydroxy-5-methylbenzamido)cyclohexyl)nicotinamide], and cilomilast, and it was comparable to GSK256066 [6-((3-(dimethylcarbamoyl)phenyl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinoline-3-carboxamide]. When administered intratracheally to rats as a micronized dry powder, CHF6001 inhibited liposaccharide-induced pulmonary neutrophilia (ED50 = 0.205 μmol/kg) and leukocyte infiltration (ED50 = 0.188 μmol/kg) with an efficacy comparable to a high dose of budesonide (1 μmol/kg i.p.). In sum, CHF6001 has the potential to be an effective topical treatment of conditions associated with pulmonary inflammation, including asthma and chronic obstructive pulmonary disease.

Authors+Show Affiliations

Corporate Pre-Clinical R & D, Chiesi Farmaceutici S.p.A., Parma, Italy (N.M., P.C., R.B., G.M., F.P., E.A., G.A., A.R., E.G., R.D.F., Ca.C., L.C., Ch.C., R.P. M.D., M.C., G.V., F.F.); Molecular Biotechnology Center, University of Turin, Turin, Italy (E.H.); and Dipartimento di Scienze Farmacologiche e Biomolecolari, Milan, Italy (C.B., A.S.).Corporate Pre-Clinical R & D, Chiesi Farmaceutici S.p.A., Parma, Italy (N.M., P.C., R.B., G.M., F.P., E.A., G.A., A.R., E.G., R.D.F., Ca.C., L.C., Ch.C., R.P. M.D., M.C., G.V., F.F.); Molecular Biotechnology Center, University of Turin, Turin, Italy (E.H.); and Dipartimento di Scienze Farmacologiche e Biomolecolari, Milan, Italy (C.B., A.S.).Corporate Pre-Clinical R & D, Chiesi Farmaceutici S.p.A., Parma, Italy (N.M., P.C., R.B., G.M., F.P., E.A., G.A., A.R., E.G., R.D.F., Ca.C., L.C., Ch.C., R.P. M.D., M.C., G.V., F.F.); Molecular Biotechnology Center, University of Turin, Turin, Italy (E.H.); and Dipartimento di Scienze Farmacologiche e Biomolecolari, Milan, Italy (C.B., A.S.).Corporate Pre-Clinical R & D, Chiesi Farmaceutici S.p.A., Parma, Italy (N.M., P.C., R.B., G.M., F.P., E.A., G.A., A.R., E.G., R.D.F., Ca.C., L.C., Ch.C., R.P. M.D., M.C., G.V., F.F.); Molecular Biotechnology Center, University of Turin, Turin, Italy (E.H.); and Dipartimento di Scienze Farmacologiche e Biomolecolari, Milan, Italy (C.B., A.S.).Corporate Pre-Clinical R & D, Chiesi Farmaceutici S.p.A., Parma, Italy (N.M., P.C., R.B., G.M., F.P., E.A., G.A., A.R., E.G., R.D.F., Ca.C., L.C., Ch.C., R.P. M.D., M.C., G.V., F.F.); Molecular Biotechnology Center, University of Turin, Turin, Italy (E.H.); and Dipartimento di Scienze Farmacologiche e Biomolecolari, Milan, Italy (C.B., A.S.).Corporate Pre-Clinical R & D, Chiesi Farmaceutici S.p.A., Parma, Italy (N.M., P.C., R.B., G.M., F.P., E.A., G.A., A.R., E.G., R.D.F., Ca.C., L.C., Ch.C., R.P. M.D., M.C., G.V., F.F.); Molecular Biotechnology Center, University of Turin, Turin, Italy (E.H.); and Dipartimento di Scienze Farmacologiche e Biomolecolari, Milan, Italy (C.B., A.S.).Corporate Pre-Clinical R & D, Chiesi Farmaceutici S.p.A., Parma, Italy (N.M., P.C., R.B., G.M., F.P., E.A., G.A., A.R., E.G., R.D.F., Ca.C., L.C., Ch.C., R.P. M.D., M.C., G.V., F.F.); Molecular Biotechnology Center, University of Turin, Turin, Italy (E.H.); and Dipartimento di Scienze Farmacologiche e Biomolecolari, Milan, Italy (C.B., A.S.).Corporate Pre-Clinical R & D, Chiesi Farmaceutici S.p.A., Parma, Italy (N.M., P.C., R.B., G.M., F.P., E.A., G.A., A.R., E.G., R.D.F., Ca.C., L.C., Ch.C., R.P. M.D., M.C., G.V., F.F.); Molecular Biotechnology Center, University of Turin, Turin, Italy (E.H.); and Dipartimento di Scienze Farmacologiche e Biomolecolari, Milan, Italy (C.B., A.S.).Corporate Pre-Clinical R & D, Chiesi Farmaceutici S.p.A., Parma, Italy (N.M., P.C., R.B., G.M., F.P., E.A., G.A., A.R., E.G., R.D.F., Ca.C., L.C., Ch.C., R.P. M.D., M.C., G.V., F.F.); Molecular Biotechnology Center, University of Turin, Turin, Italy (E.H.); and Dipartimento di Scienze Farmacologiche e Biomolecolari, Milan, Italy (C.B., A.S.).Corporate Pre-Clinical R & D, Chiesi Farmaceutici S.p.A., Parma, Italy (N.M., P.C., R.B., G.M., F.P., E.A., G.A., A.R., E.G., R.D.F., Ca.C., L.C., Ch.C., R.P. M.D., M.C., G.V., F.F.); Molecular Biotechnology Center, University of Turin, Turin, Italy (E.H.); and Dipartimento di Scienze Farmacologiche e Biomolecolari, Milan, Italy (C.B., A.S.).Corporate Pre-Clinical R & D, Chiesi Farmaceutici S.p.A., Parma, Italy (N.M., P.C., R.B., G.M., F.P., E.A., G.A., A.R., E.G., R.D.F., Ca.C., L.C., Ch.C., R.P. M.D., M.C., G.V., F.F.); Molecular Biotechnology Center, University of Turin, Turin, Italy (E.H.); and Dipartimento di Scienze Farmacologiche e Biomolecolari, Milan, Italy (C.B., A.S.).Corporate Pre-Clinical R & D, Chiesi Farmaceutici S.p.A., Parma, Italy (N.M., P.C., R.B., G.M., F.P., E.A., G.A., A.R., E.G., R.D.F., Ca.C., L.C., Ch.C., R.P. M.D., M.C., G.V., F.F.); Molecular Biotechnology Center, University of Turin, Turin, Italy (E.H.); and Dipartimento di Scienze Farmacologiche e Biomolecolari, Milan, Italy (C.B., A.S.).Corporate Pre-Clinical R & D, Chiesi Farmaceutici S.p.A., Parma, Italy (N.M., P.C., R.B., G.M., F.P., E.A., G.A., A.R., E.G., R.D.F., Ca.C., L.C., Ch.C., R.P. M.D., M.C., G.V., F.F.); Molecular Biotechnology Center, University of Turin, Turin, Italy (E.H.); and Dipartimento di Scienze Farmacologiche e Biomolecolari, Milan, Italy (C.B., A.S.).Corporate Pre-Clinical R & D, Chiesi Farmaceutici S.p.A., Parma, Italy (N.M., P.C., R.B., G.M., F.P., E.A., G.A., A.R., E.G., R.D.F., Ca.C., L.C., Ch.C., R.P. M.D., M.C., G.V., F.F.); Molecular Biotechnology Center, University of Turin, Turin, Italy (E.H.); and Dipartimento di Scienze Farmacologiche e Biomolecolari, Milan, Italy (C.B., A.S.).Corporate Pre-Clinical R & D, Chiesi Farmaceutici S.p.A., Parma, Italy (N.M., P.C., R.B., G.M., F.P., E.A., G.A., A.R., E.G., R.D.F., Ca.C., L.C., Ch.C., R.P. M.D., M.C., G.V., F.F.); Molecular Biotechnology Center, University of Turin, Turin, Italy (E.H.); and Dipartimento di Scienze Farmacologiche e Biomolecolari, Milan, Italy (C.B., A.S.).Corporate Pre-Clinical R & D, Chiesi Farmaceutici S.p.A., Parma, Italy (N.M., P.C., R.B., G.M., F.P., E.A., G.A., A.R., E.G., R.D.F., Ca.C., L.C., Ch.C., R.P. M.D., M.C., G.V., F.F.); Molecular Biotechnology Center, University of Turin, Turin, Italy (E.H.); and Dipartimento di Scienze Farmacologiche e Biomolecolari, Milan, Italy (C.B., A.S.).Corporate Pre-Clinical R & D, Chiesi Farmaceutici S.p.A., Parma, Italy (N.M., P.C., R.B., G.M., F.P., E.A., G.A., A.R., E.G., R.D.F., Ca.C., L.C., Ch.C., R.P. M.D., M.C., G.V., F.F.); Molecular Biotechnology Center, University of Turin, Turin, Italy (E.H.); and Dipartimento di Scienze Farmacologiche e Biomolecolari, Milan, Italy (C.B., A.S.).Corporate Pre-Clinical R & D, Chiesi Farmaceutici S.p.A., Parma, Italy (N.M., P.C., R.B., G.M., F.P., E.A., G.A., A.R., E.G., R.D.F., Ca.C., L.C., Ch.C., R.P. M.D., M.C., G.V., F.F.); Molecular Biotechnology Center, University of Turin, Turin, Italy (E.H.); and Dipartimento di Scienze Farmacologiche e Biomolecolari, Milan, Italy (C.B., A.S.).Corporate Pre-Clinical R & D, Chiesi Farmaceutici S.p.A., Parma, Italy (N.M., P.C., R.B., G.M., F.P., E.A., G.A., A.R., E.G., R.D.F., Ca.C., L.C., Ch.C., R.P. M.D., M.C., G.V., F.F.); Molecular Biotechnology Center, University of Turin, Turin, Italy (E.H.); and Dipartimento di Scienze Farmacologiche e Biomolecolari, Milan, Italy (C.B., A.S.).Corporate Pre-Clinical R & D, Chiesi Farmaceutici S.p.A., Parma, Italy (N.M., P.C., R.B., G.M., F.P., E.A., G.A., A.R., E.G., R.D.F., Ca.C., L.C., Ch.C., R.P. M.D., M.C., G.V., F.F.); Molecular Biotechnology Center, University of Turin, Turin, Italy (E.H.); and Dipartimento di Scienze Farmacologiche e Biomolecolari, Milan, Italy (C.B., A.S.).Corporate Pre-Clinical R & D, Chiesi Farmaceutici S.p.A., Parma, Italy (N.M., P.C., R.B., G.M., F.P., E.A., G.A., A.R., E.G., R.D.F., Ca.C., L.C., Ch.C., R.P. M.D., M.C., G.V., F.F.); Molecular Biotechnology Center, University of Turin, Turin, Italy (E.H.); and Dipartimento di Scienze Farmacologiche e Biomolecolari, Milan, Italy (C.B., A.S.) f.facchinetti@chiesi.com.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25576075

Citation

Moretto, Nadia, et al. "CHF6001 I: a Novel Highly Potent and Selective Phosphodiesterase 4 Inhibitor With Robust Anti-inflammatory Activity and Suitable for Topical Pulmonary Administration." The Journal of Pharmacology and Experimental Therapeutics, vol. 352, no. 3, 2015, pp. 559-67.
Moretto N, Caruso P, Bosco R, et al. CHF6001 I: a novel highly potent and selective phosphodiesterase 4 inhibitor with robust anti-inflammatory activity and suitable for topical pulmonary administration. J Pharmacol Exp Ther. 2015;352(3):559-67.
Moretto, N., Caruso, P., Bosco, R., Marchini, G., Pastore, F., Armani, E., ... Facchinetti, F. (2015). CHF6001 I: a novel highly potent and selective phosphodiesterase 4 inhibitor with robust anti-inflammatory activity and suitable for topical pulmonary administration. The Journal of Pharmacology and Experimental Therapeutics, 352(3), pp. 559-67. doi:10.1124/jpet.114.220541.
Moretto N, et al. CHF6001 I: a Novel Highly Potent and Selective Phosphodiesterase 4 Inhibitor With Robust Anti-inflammatory Activity and Suitable for Topical Pulmonary Administration. J Pharmacol Exp Ther. 2015;352(3):559-67. PubMed PMID: 25576075.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - CHF6001 I: a novel highly potent and selective phosphodiesterase 4 inhibitor with robust anti-inflammatory activity and suitable for topical pulmonary administration. AU - Moretto,Nadia, AU - Caruso,Paola, AU - Bosco,Raffaella, AU - Marchini,Gessica, AU - Pastore,Fiorella, AU - Armani,Elisabetta, AU - Amari,Gabriele, AU - Rizzi,Andrea, AU - Ghidini,Eleonora, AU - De Fanti,Renato, AU - Capaldi,Carmelida, AU - Carzaniga,Laura, AU - Hirsch,Emilio, AU - Buccellati,Carola, AU - Sala,Angelo, AU - Carnini,Chiara, AU - Patacchini,Riccardo, AU - Delcanale,Maurizio, AU - Civelli,Maurizio, AU - Villetti,Gino, AU - Facchinetti,Fabrizio, Y1 - 2015/01/09/ PY - 2015/1/11/entrez PY - 2015/1/13/pubmed PY - 2015/4/1/medline SP - 559 EP - 67 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 352 IS - 3 N2 - This study examined the pharmacologic characterization of CHF6001 [(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-(cyclopropylmethoxy)-4-(methylsulfonamido)benzoyloxy)ethyl)pyridine 1-oxide], a novel phosphodiesterase (PDE)4 inhibitor designed for treating pulmonary inflammatory diseases via inhaled administration. CHF6001 was 7- and 923-fold more potent than roflumilast and cilomilast, respectively, in inhibiting PDE4 enzymatic activity (IC50 = 0.026 ± 0.006 nM). CHF6001 inhibited PDE4 isoforms A-D with equal potency, showed an elevated ratio of high-affinity rolipram binding site versus low-affinity rolipram binding site (i.e., >40) and displayed >20,000-fold selectivity versus PDE4 compared with a panel of PDEs. CHF6001 effectively inhibited (subnanomolar IC50 values) the release of tumor necrosis factor-α from human peripheral blood mononuclear cells, human acute monocytic leukemia cell line macrophages (THP-1), and rodent macrophages (RAW264.7 and NR8383). Moreover, CHF6001 potently inhibited the activation of oxidative burst in neutrophils and eosinophils, neutrophil chemotaxis, and the release of interferon-γ from CD4(+) T cells. In all these functional assays, CHF6001 was more potent than previously described PDE4 inhibitors, including roflumilast, UK-500,001 [2-(3,4-difluorophenoxy)-5-fluoro-N-((1S,4S)-4-(2-hydroxy-5-methylbenzamido)cyclohexyl)nicotinamide], and cilomilast, and it was comparable to GSK256066 [6-((3-(dimethylcarbamoyl)phenyl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinoline-3-carboxamide]. When administered intratracheally to rats as a micronized dry powder, CHF6001 inhibited liposaccharide-induced pulmonary neutrophilia (ED50 = 0.205 μmol/kg) and leukocyte infiltration (ED50 = 0.188 μmol/kg) with an efficacy comparable to a high dose of budesonide (1 μmol/kg i.p.). In sum, CHF6001 has the potential to be an effective topical treatment of conditions associated with pulmonary inflammation, including asthma and chronic obstructive pulmonary disease. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/25576075/CHF6001_I:_a_novel_highly_potent_and_selective_phosphodiesterase_4_inhibitor_with_robust_anti_inflammatory_activity_and_suitable_for_topical_pulmonary_administration_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=25576075 DB - PRIME DP - Unbound Medicine ER -