Synthesis and evaluation of carbamoylmethylene linked prodrugs of BMS-582949, a clinical p38α inhibitor

Bioorg Med Chem Lett. 2013 May 15;23(10):3028-33. doi: 10.1016/j.bmcl.2013.03.022. Epub 2013 Mar 15.

Abstract

A series of carbamoylmethylene linked prodrugs of 1 (BMS-582949), a clinical p38α inhibitor, were synthesized and evaluated. Though the phosphoryloxymethylene carbamates (3, 4, and 5) and α-aminoacyloxymethylene carbamates (22, 23, and 26) were found unstable at neutral pH values, fumaric acid derived acyloxymethylene carbamates (2, 28, and 31) were highly stable under both acidic and neutral conditions. Prodrugs 2 and 31 were also highly soluble at both acidic and neutral pH values. At a solution dose of 14.2mpk (equivalent to 10mpk of 1), 2 gave essentially the same exposure of 1 compared to dosing 10mpk of 1 itself. At a suspension dose of 142mpk (equivalent to 100mpk of 1), 2 demonstrated that it could overcome the solubility issue associated with 1 and provide a much higher exposure of 1. To our knowledge, the unique type of prodrugs like 2, 28, and 31 was not reported in the past and could represent a novel prodrug approach for secondary amides, a class of molecules frequently identified as drug candidates.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Crystallography, X-Ray
  • Dacarbazine / analogs & derivatives*
  • Dacarbazine / chemistry
  • Dose-Response Relationship, Drug
  • Hydrogen-Ion Concentration
  • Models, Molecular
  • Molecular Structure
  • Prodrugs / administration & dosage
  • Prodrugs / chemical synthesis
  • Prodrugs / pharmacology*
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrroles / administration & dosage
  • Pyrroles / chemical synthesis
  • Pyrroles / pharmacology*
  • Rats
  • Solubility
  • Structure-Activity Relationship
  • Temperature
  • Triazines / administration & dosage
  • Triazines / chemical synthesis
  • Triazines / pharmacology*
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • 4-(5-(cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N-propylpyrrolo(1,2-f)(1,2,4)triazine-6-carboxamide
  • Prodrugs
  • Protein Kinase Inhibitors
  • Pyrroles
  • Triazines
  • Dacarbazine
  • p38 Mitogen-Activated Protein Kinases