title: Orally available stilbene derivatives as potent HDAC inhibitors with antiproliferative activities and antitumor effects in human tumor xenografts.
abstract: Herein we report the synthesis and activity of a novel class of HDAC inhibitors based on 2, 3-diphenyl acrylic acid derivatives. The compounds in this series have shown to be potent HDAC inhibitors possessing significant antiproliferative activity. Further compounds in this series were subjected to metabolic stability in human liver microsomes (HLM), mouse liver microsomes (MLM), and exhibits promising stability in both. These efforts culminated with the identification of a developmental candidate (5a), which displayed desirable PK/PD relationships, significant efficacy in the xenograft models and attractive ADME profiles.
authors.affiliation: Department of Chemistry, Orchid Chemicals & Pharmaceuticals Ltd, Chennai 600119, India. Electronic address: kvirendra@orchidpharma.com.
authors.forename: Virendra
authors.initials: V
authors.lastname: Kachhadia
authors.affiliation: Department of Chemistry, Orchid Chemicals & Pharmaceuticals Ltd, Chennai 600119, India.
authors.forename: Sridharan
authors.initials: S
authors.lastname: Rajagopal
authors.affiliation: Department of Chemistry, Orchid Chemicals & Pharmaceuticals Ltd, Chennai 600119, India.
authors.forename: Thanasekaran
authors.initials: T
authors.lastname: Ponpandian
authors.affiliation: Department of Chemistry, Orchid Chemicals & Pharmaceuticals Ltd, Chennai 600119, India.
authors.forename: Radhakrishnan
authors.initials: R
authors.lastname: Vignesh
authors.affiliation: Department of Chemistry, Orchid Chemicals & Pharmaceuticals Ltd, Chennai 600119, India.
authors.forename: Karnambaram
authors.initials: K
authors.lastname: Anandhan
authors.affiliation: Department of Biology, Drug Discovery Research, Orchid Chemicals & Pharmaceuticals Ltd, Chennai 600119, India.
authors.forename: Daivasigamani
authors.initials: D
authors.lastname: Prabhu
authors.affiliation: Department of Biology, Drug Discovery Research, Orchid Chemicals & Pharmaceuticals Ltd, Chennai 600119, India.
authors.forename: Praveen
authors.initials: P
authors.lastname: Rajendran
authors.affiliation: Department of Biology, Drug Discovery Research, Orchid Chemicals & Pharmaceuticals Ltd, Chennai 600119, India.
authors.forename: Saranya
authors.initials: S
authors.lastname: Nidhyanandan
authors.affiliation: Department of Biology, Drug Discovery Research, Orchid Chemicals & Pharmaceuticals Ltd, Chennai 600119, India.
authors.forename: Anshu Mittal
authors.initials: AM
authors.lastname: Roy
authors.affiliation: Department of Biology, Drug Discovery Research, Orchid Chemicals & Pharmaceuticals Ltd, Chennai 600119, India.
authors.forename: Fakrudeen Ali
authors.initials: FA
authors.lastname: Ahamed
authors.affiliation: Department of Biology, Drug Discovery Research, Orchid Chemicals & Pharmaceuticals Ltd, Chennai 600119, India.
authors.forename: Narayanan
authors.initials: N
authors.lastname: Surendran
authors.affiliation: Department of Biology, Drug Discovery Research, Orchid Chemicals & Pharmaceuticals Ltd, Chennai 600119, India.
authors.forename: Sriram
authors.initials: S
authors.lastname: Rajagopal
authors.affiliation: Fondation for Neglected Disease Research, Yelahanka, Bangalore 562157, India.
authors.forename: Shridhar
authors.initials: S
authors.lastname: Narayanan
authors.affiliation: Department of Chemistry, Orchid Chemicals & Pharmaceuticals Ltd, Chennai 600119, India.
authors.forename: Balasubramanian
authors.initials: B
authors.lastname: Gopalan
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002934:Cinnamates / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D013267:Stilbenes / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D002934:Cinnamates; D056572:Histone Deacetylase Inhibitors; D013267:Stilbenes; D006655:Histone Deacetylases
keywords: Antiproliferative activity; Benzamide; Histone deacetylases; Hydroxamate; Stilbene