Design and synthesis of polyethylene glycol-modified biphenylsulfonyl- thiophene-carboxamidine inhibitors of the complement component C1s

Nalin L. Subasinghe; Ehab Khalil; Jeremy M. Travins; Farah Ali; Shelley K. Ballentine; Heather R. Hufnagel; Wenxi Pan; Kristi Leonard; Roger F. Bone; Richard M. Soll; Carl S. Crysler; Nisha Ninan; Jennifer Kirkpatrick; Michael X. Kolpak; Karen A. Diloreto; Stephen H. Eisennagel; Norman D. Huebert; Christopher J. Molloy; Bruce E. Tomczuk; Michael D. Gaul

doi:10.1016/j.bmcl.2012.06.030

Design and synthesis of polyethylene glycol-modified biphenylsulfonyl- thiophene-carboxamidine inhibitors of the complement component C1s

Nalin L. Subasinghe, Ehab Khalil, Jeremy M. Travins, Farah Ali, Shelley K. Ballentine, Heather R. Hufnagel, Wenxi Pan, Kristi Leonard, Roger F. Bone, Richard M. Soll, Carl S. Crysler, Nisha Ninan, Jennifer Kirkpatrick, Michael X. Kolpak, Karen A. Diloreto, Stephen H. Eisennagel, Norman D. Huebert, Christopher J. Molloy, Bruce E. Tomczuk, Michael D. Gaul

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

7 Scopus citations

Abstract

Complement C1s protease inhibitors have potential utility in the treatment of diseases associated with activation of the classical complement pathway such as humorally mediated graft rejection, ischemia-reperfusion injury (IRI), vascular leak syndrome, and acute respiratory distress syndrome (ARDS). The utility of biphenylsulfonyl-thiophene-carboxamidine small-molecule C1s inhibitors are limited by their poor in vivo pharmacokinetic properties. Pegylation of a potent analog has provided compounds with good potency and good in vivo pharmacokinetic properties.

Original language	English (US)
Pages (from-to)	5303-5307
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	22
Issue number	16
DOIs	https://doi.org/10.1016/j.bmcl.2012.06.030
State	Published - Aug 15 2012
Externally published	Yes

All Science Journal Classification (ASJC) codes

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

Keywords

C1s inhibitors
Complement inhibitors
Pegylated molecule PK
Pegylated molecule pharmacokinetics
Pegylated small molecule
Pegylation
Pharmacokinetics
Polyethylene glycol-modified
Polyethylene glycol-modified small molecule

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10.1016/j.bmcl.2012.06.030

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Subasinghe, N. L., Khalil, E., Travins, J. M., Ali, F., Ballentine, S. K., Hufnagel, H. R., Pan, W., Leonard, K., Bone, R. F., Soll, R. M., Crysler, C. S., Ninan, N., Kirkpatrick, J., Kolpak, M. X., Diloreto, K. A., Eisennagel, S. H., Huebert, N. D., Molloy, C. J., Tomczuk, B. E., & Gaul, M. D. (2012). Design and synthesis of polyethylene glycol-modified biphenylsulfonyl- thiophene-carboxamidine inhibitors of the complement component C1s. Bioorganic and Medicinal Chemistry Letters, 22(16), 5303-5307. https://doi.org/10.1016/j.bmcl.2012.06.030

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title = "Design and synthesis of polyethylene glycol-modified biphenylsulfonyl- thiophene-carboxamidine inhibitors of the complement component C1s",

abstract = "Complement C1s protease inhibitors have potential utility in the treatment of diseases associated with activation of the classical complement pathway such as humorally mediated graft rejection, ischemia-reperfusion injury (IRI), vascular leak syndrome, and acute respiratory distress syndrome (ARDS). The utility of biphenylsulfonyl-thiophene-carboxamidine small-molecule C1s inhibitors are limited by their poor in vivo pharmacokinetic properties. Pegylation of a potent analog has provided compounds with good potency and good in vivo pharmacokinetic properties.",

keywords = "C1s inhibitors, Complement inhibitors, Pegylated molecule PK, Pegylated molecule pharmacokinetics, Pegylated small molecule, Pegylation, Pharmacokinetics, Polyethylene glycol-modified, Polyethylene glycol-modified small molecule",

author = "Subasinghe, {Nalin L.} and Ehab Khalil and Travins, {Jeremy M.} and Farah Ali and Ballentine, {Shelley K.} and Hufnagel, {Heather R.} and Wenxi Pan and Kristi Leonard and Bone, {Roger F.} and Soll, {Richard M.} and Crysler, {Carl S.} and Nisha Ninan and Jennifer Kirkpatrick and Kolpak, {Michael X.} and Diloreto, {Karen A.} and Eisennagel, {Stephen H.} and Huebert, {Norman D.} and Molloy, {Christopher J.} and Tomczuk, {Bruce E.} and Gaul, {Michael D.}",

year = "2012",

month = aug,

day = "15",

doi = "10.1016/j.bmcl.2012.06.030",

language = "English (US)",

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journal = "Bioorganic and Medicinal Chemistry Letters",

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Subasinghe, NL, Khalil, E, Travins, JM, Ali, F, Ballentine, SK, Hufnagel, HR, Pan, W, Leonard, K, Bone, RF, Soll, RM, Crysler, CS, Ninan, N, Kirkpatrick, J, Kolpak, MX, Diloreto, KA, Eisennagel, SH, Huebert, ND, Molloy, CJ, Tomczuk, BE & Gaul, MD 2012, 'Design and synthesis of polyethylene glycol-modified biphenylsulfonyl- thiophene-carboxamidine inhibitors of the complement component C1s', Bioorganic and Medicinal Chemistry Letters, vol. 22, no. 16, pp. 5303-5307. https://doi.org/10.1016/j.bmcl.2012.06.030

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T1 - Design and synthesis of polyethylene glycol-modified biphenylsulfonyl- thiophene-carboxamidine inhibitors of the complement component C1s

AU - Subasinghe, Nalin L.

AU - Khalil, Ehab

AU - Travins, Jeremy M.

AU - Ali, Farah

AU - Ballentine, Shelley K.

AU - Hufnagel, Heather R.

AU - Pan, Wenxi

AU - Leonard, Kristi

AU - Bone, Roger F.

AU - Soll, Richard M.

AU - Crysler, Carl S.

AU - Ninan, Nisha

AU - Kirkpatrick, Jennifer

AU - Kolpak, Michael X.

AU - Diloreto, Karen A.

AU - Eisennagel, Stephen H.

AU - Huebert, Norman D.

AU - Molloy, Christopher J.

AU - Tomczuk, Bruce E.

AU - Gaul, Michael D.

PY - 2012/8/15

Y1 - 2012/8/15

N2 - Complement C1s protease inhibitors have potential utility in the treatment of diseases associated with activation of the classical complement pathway such as humorally mediated graft rejection, ischemia-reperfusion injury (IRI), vascular leak syndrome, and acute respiratory distress syndrome (ARDS). The utility of biphenylsulfonyl-thiophene-carboxamidine small-molecule C1s inhibitors are limited by their poor in vivo pharmacokinetic properties. Pegylation of a potent analog has provided compounds with good potency and good in vivo pharmacokinetic properties.

AB - Complement C1s protease inhibitors have potential utility in the treatment of diseases associated with activation of the classical complement pathway such as humorally mediated graft rejection, ischemia-reperfusion injury (IRI), vascular leak syndrome, and acute respiratory distress syndrome (ARDS). The utility of biphenylsulfonyl-thiophene-carboxamidine small-molecule C1s inhibitors are limited by their poor in vivo pharmacokinetic properties. Pegylation of a potent analog has provided compounds with good potency and good in vivo pharmacokinetic properties.

KW - C1s inhibitors

KW - Complement inhibitors

KW - Pegylated molecule PK

KW - Pegylated molecule pharmacokinetics

KW - Pegylated small molecule

KW - Pegylation

KW - Pharmacokinetics

KW - Polyethylene glycol-modified

KW - Polyethylene glycol-modified small molecule

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JO - Bioorganic and Medicinal Chemistry Letters

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IS - 16

ER -

Design and synthesis of polyethylene glycol-modified biphenylsulfonyl- thiophene-carboxamidine inhibitors of the complement component C1s

Abstract

All Science Journal Classification (ASJC) codes

Keywords

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