title: Insulin-like growth factor-1 receptor (IGF-1R) kinase inhibitors: SAR of a series of 3-[6-(4-substituted-piperazin-1-yl)-4-methyl-1H-benzimidazol-2-yl]-1H-pyridine-2-one.
abstract: A series of 3-[6-(4-substituted-piperazin-1-yl)-4-methyl-1H-benzimidazol-2-yl]-1H-pyridine-2-one were synthesized to modulate CYP3A4 inhibition and improve aqueous solubility of our prototypical compound BMS-536924 (1), while maintaining potent IGF-1R inhibitory activity. Structure-activity and structure-solubility studies led to the identification of BMS-577098 (27), which demonstrates oral in vivo efficacy in animal models. The improvement was achieved by replacing morpholine with more polar bio-isoster piperazine and modulating the basicity of distal nitrogen with appropriate substitutions.
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb Company, Wallingford, CT 06492, USA. upender.velaparthi@bms.com
authors.forename: Upender
authors.initials: U
authors.lastname: Velaparthi
authors.forename: Mark G
authors.initials: MG
authors.lastname: Saulnier
authors.forename: Mark D
authors.initials: MD
authors.lastname: Wittman
authors.forename: Peiying
authors.initials: P
authors.lastname: Liu
authors.forename: David B
authors.initials: DB
authors.lastname: Frennesson
authors.forename: Kurt
authors.initials: K
authors.lastname: Zimmermann
authors.forename: Joan M
authors.initials: JM
authors.lastname: Carboni
authors.forename: Marco
authors.initials: M
authors.lastname: Gottardis
authors.forename: Aixin
authors.initials: A
authors.lastname: Li
authors.forename: Ann
authors.initials: A
authors.lastname: Greer
authors.forename: Wendy
authors.initials: W
authors.lastname: Clarke
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yang
authors.forename: Krista
authors.initials: K
authors.lastname: Menard
authors.forename: Francis Y
authors.initials: FY
authors.lastname: Lee
authors.forename: George
authors.initials: G
authors.lastname: Trainor
authors.forename: Dolatrai
authors.initials: D
authors.lastname: Vyas
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: C504983:BMS 536924; C551144:BMS 577098; D001562:Benzimidazoles; D065692:Cytochrome P-450 CYP3A Inhibitors; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011728:Pyridones; C031000:benzimidazole; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D017526:Receptor, IGF Type 1