Search

Your search keyword '"Everlof, Gerry"' showing total 2 results
Start Over Author "Everlof, Gerry" Topic prodrugs
2 results on '"Everlof, Gerry"'

1. 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.

Author

Liu C, Lin J, Hynes J, Wu H, Wrobleski ST, Lin S, Dhar TG, Vrudhula VM, Sun JH, Chao S, Zhao R, Wang B, Chen BC, Everlof G, Gesenberg C, Zhang H, Marathe PH, McIntyre KW, Taylor TL, Gillooly K, Shuster DJ, McKinnon M, Dodd JH, Barrish JC, Schieven GL, and Leftheris K

Subjects
Administration, Oral, Animals, Arthritis, Experimental drug therapy, Biological Availability, Chemistry Techniques, Synthetic, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical methods, Macaca fascicularis, Male, Mitogen-Activated Protein Kinase 14 antagonists & inhibitors, Molecular Structure, Organophosphates chemistry, Phenylacetates chemistry, Prodrugs pharmacokinetics, Protein Kinase Inhibitors chemistry, Rats, Inbred Lew, Rats, Sprague-Dawley, Solubility, Structure-Activity Relationship, Organophosphates pharmacology, Phenylacetates pharmacology, Prodrugs chemistry, Prodrugs pharmacology, Protein Kinase Inhibitors pharmacology
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.

Published
2015
Full Text
View/download PDF

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

Author

Liu C, Lin J, Everlof G, Gesenberg C, Zhang H, Marathe PH, Malley M, Galella MA, McKinnon M, Dodd JH, Barrish JC, Schieven GL, and Leftheris K

Subjects
Animals, Crystallography, X-Ray, Dacarbazine chemistry, Dose-Response Relationship, Drug, Hydrogen-Ion Concentration, Models, Molecular, Molecular Structure, Prodrugs administration & dosage, Prodrugs chemical synthesis, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors chemical synthesis, Pyrroles administration & dosage, Pyrroles chemical synthesis, Rats, Solubility, Structure-Activity Relationship, Temperature, Triazines administration & dosage, Triazines chemical synthesis, p38 Mitogen-Activated Protein Kinases metabolism, Dacarbazine analogs & derivatives, Prodrugs pharmacology, Protein Kinase Inhibitors pharmacology, Pyrroles pharmacology, Triazines pharmacology, p38 Mitogen-Activated Protein Kinases antagonists & inhibitors
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., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Published
2013
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results