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

Chunjian Liu; James Lin; Gerry Everlof; Christoph Gesenberg; Hongjian Zhang; Punit H. Marathe; Mary Malley; Michael A. Galella; Murray McKinnon; John H. Dodd; Joel C. Barrish; Gary L. Schieven; Katerina Leftheris

doi:10.1016/j.bmcl.2013.03.022

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

Chunjian Liu, James Lin, Gerry Everlof, Christoph Gesenberg, Hongjian Zhang, Punit H. Marathe, Mary Malley, Michael A. Galella, Murray McKinnon, John H. Dodd, Joel C. Barrish, Gary L. Schieven, Katerina Leftheris

Chemistry

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

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 14.2 mpk (equivalent to 10 mpk of 1), 2 gave essentially the same exposure of 1 compared to dosing 10 mpk of 1 itself. At a suspension dose of 142 mpk (equivalent to 100 mpk 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.

Original language	English (US)
Pages (from-to)	3028-3033
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	23
Issue number	10
DOIs	https://doi.org/10.1016/j.bmcl.2013.03.022
State	Published - May 15 2013

All Science Journal Classification (ASJC) codes

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

Access to Document

10.1016/j.bmcl.2013.03.022

Cite this

Liu, C., Lin, J., Everlof, G., Gesenberg, C., Zhang, H., Marathe, P. H., Malley, M., Galella, M. A., McKinnon, M., Dodd, J. H., Barrish, J. C., Schieven, G. L., & Leftheris, K. (2013). Synthesis and evaluation of carbamoylmethylene linked prodrugs of BMS-582949, a clinical p38α inhibitor. Bioorganic and Medicinal Chemistry Letters, 23(10), 3028-3033. https://doi.org/10.1016/j.bmcl.2013.03.022

@article{8daf2892c4dc4b23a5f05af1aea9af4c,

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

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 14.2 mpk (equivalent to 10 mpk of 1), 2 gave essentially the same exposure of 1 compared to dosing 10 mpk of 1 itself. At a suspension dose of 142 mpk (equivalent to 100 mpk 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.",

author = "Chunjian Liu and James Lin and Gerry Everlof and Christoph Gesenberg and Hongjian Zhang and Marathe, {Punit H.} and Mary Malley and Galella, {Michael A.} and Murray McKinnon and Dodd, {John H.} and Barrish, {Joel C.} and Schieven, {Gary L.} and Katerina Leftheris",

year = "2013",

month = may,

day = "15",

doi = "10.1016/j.bmcl.2013.03.022",

language = "English (US)",

volume = "23",

pages = "3028--3033",

journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

publisher = "Elsevier Ltd",

number = "10",

}

Liu, C, Lin, J, Everlof, G, Gesenberg, C, Zhang, H, Marathe, PH, Malley, M, Galella, MA, McKinnon, M, Dodd, JH, Barrish, JC, Schieven, GL & Leftheris, K 2013, 'Synthesis and evaluation of carbamoylmethylene linked prodrugs of BMS-582949, a clinical p38α inhibitor', Bioorganic and Medicinal Chemistry Letters, vol. 23, no. 10, pp. 3028-3033. https://doi.org/10.1016/j.bmcl.2013.03.022

TY - JOUR

T1 - Synthesis and evaluation of carbamoylmethylene linked prodrugs of BMS-582949, a clinical p38α inhibitor

AU - Liu, Chunjian

AU - Lin, James

AU - Everlof, Gerry

AU - Gesenberg, Christoph

AU - Zhang, Hongjian

AU - Marathe, Punit H.

AU - Malley, Mary

AU - Galella, Michael A.

AU - McKinnon, Murray

AU - Dodd, John H.

AU - Barrish, Joel C.

AU - Schieven, Gary L.

AU - Leftheris, Katerina

PY - 2013/5/15

Y1 - 2013/5/15

N2 - 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 14.2 mpk (equivalent to 10 mpk of 1), 2 gave essentially the same exposure of 1 compared to dosing 10 mpk of 1 itself. At a suspension dose of 142 mpk (equivalent to 100 mpk 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.

AB - 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 14.2 mpk (equivalent to 10 mpk of 1), 2 gave essentially the same exposure of 1 compared to dosing 10 mpk of 1 itself. At a suspension dose of 142 mpk (equivalent to 100 mpk 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.

UR - http://www.scopus.com/inward/record.url?scp=84876692329&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84876692329&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2013.03.022

DO - 10.1016/j.bmcl.2013.03.022

M3 - Article

C2 - 23578688

AN - SCOPUS:84876692329

SN - 0960-894X

VL - 23

SP - 3028

EP - 3033

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 10

ER -

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

Abstract

All Science Journal Classification (ASJC) codes

Access to Document

Other files and links

Fingerprint

Cite this