title: In vivo effective dibenzo[b,d]furan-1-yl-thiazoles as novel PDE-4 inhibitors.
abstract: Herein we report the synthesis, PDE-4B and TNF-α inhibitory activities of a few dibenzo[b,d]furan-1-yl-thiazole derivatives. The hydroxycyclohexanol amide derivatives 14, 18, 24, 29, 31 and 33 exhibited promising in vitro PDE-4B and TNF-α inhibitory activities. Compound 24 showed good systemic availability in preclinical animal models and was also found to be non-toxic (exploratory mutagenicity test). Further it exhibited promising results in in vivo asthma/COPD and Uveitis models.
authors.affiliation: Department of Medicinal Chemistry, Drug Discovery Research, Orchid Pharma Ltd, Chennai 600119, India.
authors.forename: Gopalan
authors.initials: G
authors.lastname: Balasubramanian
authors.affiliation: Department of Medicinal Chemistry, Drug Discovery Research, Orchid Pharma Ltd, Chennai 600119, India.
authors.forename: Sukunath
authors.initials: S
authors.lastname: Narayanan
authors.affiliation: Department of Medicinal Chemistry, Drug Discovery Research, Orchid Pharma Ltd, Chennai 600119, India.
authors.forename: Lavanya
authors.initials: L
authors.lastname: Andiappan
authors.affiliation: Department of Medicinal Chemistry, Drug Discovery Research, Orchid Pharma Ltd, Chennai 600119, India.
authors.forename: Thirunavukkarasu
authors.initials: T
authors.lastname: Sappanimuthu
authors.affiliation: Department of Medicinal Chemistry, Drug Discovery Research, Orchid Pharma Ltd, Chennai 600119, India.
authors.forename: Saravanan
authors.initials: S
authors.lastname: Thirunavukkarasu
authors.affiliation: Department of Medicinal Chemistry, Drug Discovery Research, Orchid Pharma Ltd, Chennai 600119, India.
authors.forename: Shamundeeswari
authors.initials: S
authors.lastname: Sundaram
authors.affiliation: Department of Medicinal Chemistry, Drug Discovery Research, Orchid Pharma Ltd, Chennai 600119, India.
authors.forename: Saravanakumar
authors.initials: S
authors.lastname: Natarajan
authors.affiliation: Department of Medicinal Chemistry, Drug Discovery Research, Orchid Pharma Ltd, Chennai 600119, India.
authors.forename: Naresh
authors.initials: N
authors.lastname: Sivaraman
authors.affiliation: Department of Medicinal Chemistry, Drug Discovery Research, Orchid Pharma Ltd, Chennai 600119, India.
authors.forename: Sridharan
authors.initials: S
authors.lastname: Rajagopal
authors.affiliation: Department of Biology, Drug Discovery Research, Orchid Pharma Ltd, Chennai 600119, India.
authors.forename: Fakrudeen Ali Ahamed
authors.initials: FAA
authors.lastname: Nazumudeen
authors.affiliation: Department of Biology, Drug Discovery Research, Orchid Pharma Ltd, Chennai 600119, India.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Saxena
authors.affiliation: Department of Biology, Drug Discovery Research, Orchid Pharma Ltd, Chennai 600119, India.
authors.forename: Santosh L
authors.initials: SL
authors.lastname: Vishwakarma
authors.affiliation: Department of Biology, Drug Discovery Research, Orchid Pharma Ltd, Chennai 600119, India.
authors.forename: Shridhar
authors.initials: S
authors.lastname: Narayanan
authors.affiliation: Department of Medicinal Chemistry, Drug Discovery Research, Orchid Pharma Ltd, Chennai 600119, India.
authors.forename: Ganapavarapu V R
authors.initials: GVR
authors.lastname: Sharma
authors.affiliation: Department of Medicinal Chemistry, Drug Discovery Research, Orchid Pharma Ltd, Chennai 600119, India.
authors.forename: Chidambaram V
authors.initials: CV
authors.lastname: Srinivasan
authors.affiliation: Department of Medicinal Chemistry, Drug Discovery Research, Orchid Pharma Ltd, Chennai 600119, India. Electronic address: narasimhank@orchidpharma.com.
authors.forename: Narasimhan
authors.initials: N
authors.lastname: Kilambi
mesh_terms: D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D058988:Phosphodiesterase 4 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: D005663:Furans; D058988:Phosphodiesterase 4 Inhibitors; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; C000621693:dibenzo(b,d)furan-1-yl-thiazole; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4
keywords: Dibenzofuran; PDE-4 inhibitors; TNF-α