title: Discovery of thiazolyl-phthalazinone acetamides as potent glucose uptake activators via high-throughput screening.
abstract: With the aim to discover orally active small molecules that stimulate glucose uptake, high throughput screening of a library of 5000 drug-like compounds was conducted in differentiated skeletal muscle cells in presence of insulin. N-Substituted phthalazinone acetamide was identified as a potential glucose uptake modulator. Several novel derivatives were synthesized to establish structure activity relationships. Identified lead thiazolyl-phthalazinone acetamide (7114863) increased glucose uptake (EC50 of 0.07±0.02 μM) in differentiated skeletal muscle cells in presence of insulin. Furthermore, 7114863 was superior to rosiglitazone under similar experimental conditions without inducing PPAR-γ agonist activity thus making it a very interesting scaffold.
authors.affiliation: Department of Medicinal Chemistry, Piramal Enterprises Limited, 1, Nirlon Complex, Goregaon (E), Mumbai, India. Electronic address: madhavi.agrawal@piramal.com.
authors.forename: Madhavi
authors.initials: M
authors.lastname: Agrawal
authors.forename: Prashant
authors.initials: P
authors.lastname: Kharkar
authors.forename: Sonali
authors.initials: S
authors.lastname: Moghe
authors.forename: Tushar
authors.initials: T
authors.lastname: Mahajan
authors.forename: Vaishali
authors.initials: V
authors.lastname: Deka
authors.forename: Chandni
authors.initials: C
authors.lastname: Thakkar
authors.forename: Amrutha
authors.initials: A
authors.lastname: Nair
authors.forename: Chirag
authors.initials: C
authors.lastname: Mehta
authors.forename: Julie
authors.initials: J
authors.lastname: Bose
authors.forename: Asha
authors.initials: A
authors.lastname: Kulkarni-Almeida
authors.forename: Dilip
authors.initials: D
authors.lastname: Bhedi
authors.forename: Ram A
authors.initials: RA
authors.lastname: Vishwakarma
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D004353:Drug Evaluation, Preclinical; D005947:Glucose / Q000378:metabolism; D057166:High-Throughput Screening Assays; D006801:Humans; D007004:Hypoglycemic Agents; D007328:Insulin / Q000494:pharmacology; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D010793:Phthalazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C588141:2-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-N-(4-phenylthiazol-2-yl)acetamide; D000081:Acetamides; D007004:Hypoglycemic Agents; D007328:Insulin; D047495:PPAR gamma; D010793:Phthalazines; D013844:Thiazoles; D005947:Glucose
keywords: Glucose uptake activators; Obesity; PPAR-γ; Thiazolyl-phthalazinone acetamides; Type 2 diabetes