title: Discovery of ((4-(5-(Cyclopropylcarbamoyl)-2-methylphenylamino)-5-methylpyrrolo[1,2-f][1,2,4]triazine-6-carbonyl)(propyl)carbamoyloxy)methyl-2-(4-(phosphonooxy)phenyl)acetate (BMS-751324), a Clinical Prodrug of p38α MAP Kinase Inhibitor.
abstract: In search for prodrugs to address the issue of pH-dependent solubility and exposure associated with 1 (BMS-582949), a previously disclosed phase II clinical p38α MAP kinase inhibitor, a structurally novel clinical prodrug, 2 (BMS-751324), featuring a carbamoylmethylene linked promoiety containing hydroxyphenyl acetic acid (HPA) derived ester and phosphate functionalities, was identified. Prodrug 2 was not only stable but also water-soluble under both acidic and neutral conditions. It was effectively bioconverted into parent drug 1 in vivo by alkaline phosphatase and esterase in a stepwise manner, providing higher exposure of 1 compared to its direct administration, especially within higher dose ranges. In a rat LPS-induced TNFα pharmacodynamic model and a rat adjuvant arthritis model, 2 demonstrated similar efficacy to 1. Most importantly, it was shown in clinical studies that prodrug 2 was indeed effective in addressing the pH-dependent absorption issue associated with 1.
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: Chunjian
authors.initials: C
authors.lastname: Liu
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: James
authors.initials: J
authors.lastname: Lin
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: John
authors.initials: J
authors.lastname: Hynes
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Wrobleski
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: Shuqun
authors.initials: S
authors.lastname: Lin
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: T G Murali
authors.initials: TG
authors.lastname: Dhar
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: Vivekananda M
authors.initials: VM
authors.lastname: Vrudhula
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: Jung-Hui
authors.initials: JH
authors.lastname: Sun
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: Sam
authors.initials: S
authors.lastname: Chao
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: Rulin
authors.initials: R
authors.lastname: Zhao
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: Bei
authors.initials: B
authors.lastname: Wang
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: Bang-Chi
authors.initials: BC
authors.lastname: Chen
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: Gerry
authors.initials: G
authors.lastname: Everlof
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: Christoph
authors.initials: C
authors.lastname: Gesenberg
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: Hongjian
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: Punit H
authors.initials: PH
authors.lastname: Marathe
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: Kim W
authors.initials: KW
authors.lastname: McIntyre
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Taylor
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Gillooly
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: David J
authors.initials: DJ
authors.lastname: Shuster
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: Murray
authors.initials: M
authors.lastname: McKinnon
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: John H
authors.initials: JH
authors.lastname: Dodd
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: Joel C
authors.initials: JC
authors.lastname: Barrish
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: Gary L
authors.initials: GL
authors.lastname: Schieven
authors.affiliation: Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: Katerina
authors.initials: K
authors.lastname: Leftheris
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy; D001682:Biological Availability; D060326:Chemistry Techniques, Synthetic; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D008252:Macaca fascicularis; D008297:Male; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors; D015394:Molecular Structure; D010755:Organophosphates / Q000737:chemistry / Q000494:pharmacology*; D010648:Phenylacetates / Q000737:chemistry / Q000494:pharmacology*; D011355:Prodrugs / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: C000607187:((4-(5-(cyclopropylcarbamoyl)-2-methylphenylamino)-5-methylpyrrolo(1,2-f)(1,2,4)triazine-6-carbonyl)(propyl)carbamoyloxy)methyl-2-(4-(phosphonooxy)phenyl)acetate; D010755:Organophosphates; D010648:Phenylacetates; D011355:Prodrugs; D047428:Protein Kinase Inhibitors; D048308:Mitogen-Activated Protein Kinase 14