Design and Synthesis of 4,5-disubstituted-thiophene-2-amidines as potent urokinase inhibitors

M. Jonathan Rudolph; Carl R. Illig; Nalin L. Subasinghe; Kenneth J. Wilson; James B. Hoffman; Troy Randle; David Green; Chris J. Molloy; Richard M. Soll; Frank Lewandowski; Marie Zhang; Roger Bone; John C. Spurlino; Ingrid C. Deckman; Carl Manthey; Celia Sharp; Diane Maguire; Bruce L. Grasberger; Renée L. DesJarlais; Zhao Zhou

doi:10.1016/S0960-894X(01)00787-9

Design and Synthesis of 4,5-disubstituted-thiophene-2-amidines as potent urokinase inhibitors

M. Jonathan Rudolph, Carl R. Illig, Nalin L. Subasinghe, Kenneth J. Wilson, James B. Hoffman, Troy Randle, David Green, Chris J. Molloy, Richard M. Soll, Frank Lewandowski, Marie Zhang, Roger Bone, John C. Spurlino, Ingrid C. Deckman, Carl Manthey, Celia Sharp, Diane Maguire, Bruce L. Grasberger, Renée L. DesJarlais, Zhao Zhou

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33 Scopus citations

Abstract

A study of the S1 binding of lead 5-methylthiothiophene amidine 3, an inhibitor of urokinase-type plasminogen activator, was undertaken by the introduction of a variety of substituents at the thiophene 5-position. The 5-alkyl substituted and unsubstituted thiophenes were prepared using organolithium chemistry. Heteroatom substituents were introduced at the 5-position using a novel displacement reaction of 5-methylsulfonylthiophenes and the corresponding oxygen or sulfur anions. Small alkyl group substitution at the 5-position provided inhibitors equipotent with 3 but possessing improved solubility.

Original language	English (US)
Pages (from-to)	491-495
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	12
Issue number	3
DOIs	https://doi.org/10.1016/S0960-894X(01)00787-9
State	Published - Feb 11 2002
Externally published	Yes

All Science Journal Classification (ASJC) codes

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

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10.1016/S0960-894X(01)00787-9

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Rudolph, M. J., Illig, C. R., Subasinghe, N. L., Wilson, K. J., Hoffman, J. B., Randle, T., Green, D., Molloy, C. J., Soll, R. M., Lewandowski, F., Zhang, M., Bone, R., Spurlino, J. C., Deckman, I. C., Manthey, C., Sharp, C., Maguire, D., Grasberger, B. L., DesJarlais, R. L., & Zhou, Z. (2002). Design and Synthesis of 4,5-disubstituted-thiophene-2-amidines as potent urokinase inhibitors. Bioorganic and Medicinal Chemistry Letters, 12(3), 491-495. https://doi.org/10.1016/S0960-894X(01)00787-9

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title = "Design and Synthesis of 4,5-disubstituted-thiophene-2-amidines as potent urokinase inhibitors",

abstract = "A study of the S1 binding of lead 5-methylthiothiophene amidine 3, an inhibitor of urokinase-type plasminogen activator, was undertaken by the introduction of a variety of substituents at the thiophene 5-position. The 5-alkyl substituted and unsubstituted thiophenes were prepared using organolithium chemistry. Heteroatom substituents were introduced at the 5-position using a novel displacement reaction of 5-methylsulfonylthiophenes and the corresponding oxygen or sulfur anions. Small alkyl group substitution at the 5-position provided inhibitors equipotent with 3 but possessing improved solubility.",

author = "Rudolph, {M. Jonathan} and Illig, {Carl R.} and Subasinghe, {Nalin L.} and Wilson, {Kenneth J.} and Hoffman, {James B.} and Troy Randle and David Green and Molloy, {Chris J.} and Soll, {Richard M.} and Frank Lewandowski and Marie Zhang and Roger Bone and Spurlino, {John C.} and Deckman, {Ingrid C.} and Carl Manthey and Celia Sharp and Diane Maguire and Grasberger, {Bruce L.} and DesJarlais, {Ren{\'e}e L.} and Zhao Zhou",

year = "2002",

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day = "11",

doi = "10.1016/S0960-894X(01)00787-9",

language = "English (US)",

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Rudolph, MJ, Illig, CR, Subasinghe, NL, Wilson, KJ, Hoffman, JB, Randle, T, Green, D, Molloy, CJ, Soll, RM, Lewandowski, F, Zhang, M, Bone, R, Spurlino, JC, Deckman, IC, Manthey, C, Sharp, C, Maguire, D, Grasberger, BL, DesJarlais, RL & Zhou, Z 2002, 'Design and Synthesis of 4,5-disubstituted-thiophene-2-amidines as potent urokinase inhibitors', Bioorganic and Medicinal Chemistry Letters, vol. 12, no. 3, pp. 491-495. https://doi.org/10.1016/S0960-894X(01)00787-9

TY - JOUR

T1 - Design and Synthesis of 4,5-disubstituted-thiophene-2-amidines as potent urokinase inhibitors

AU - Rudolph, M. Jonathan

AU - Illig, Carl R.

AU - Subasinghe, Nalin L.

AU - Wilson, Kenneth J.

AU - Hoffman, James B.

AU - Randle, Troy

AU - Green, David

AU - Molloy, Chris J.

AU - Soll, Richard M.

AU - Lewandowski, Frank

AU - Zhang, Marie

AU - Bone, Roger

AU - Spurlino, John C.

AU - Deckman, Ingrid C.

AU - Manthey, Carl

AU - Sharp, Celia

AU - Maguire, Diane

AU - Grasberger, Bruce L.

AU - DesJarlais, Renée L.

AU - Zhou, Zhao

PY - 2002/2/11

Y1 - 2002/2/11

N2 - A study of the S1 binding of lead 5-methylthiothiophene amidine 3, an inhibitor of urokinase-type plasminogen activator, was undertaken by the introduction of a variety of substituents at the thiophene 5-position. The 5-alkyl substituted and unsubstituted thiophenes were prepared using organolithium chemistry. Heteroatom substituents were introduced at the 5-position using a novel displacement reaction of 5-methylsulfonylthiophenes and the corresponding oxygen or sulfur anions. Small alkyl group substitution at the 5-position provided inhibitors equipotent with 3 but possessing improved solubility.

AB - A study of the S1 binding of lead 5-methylthiothiophene amidine 3, an inhibitor of urokinase-type plasminogen activator, was undertaken by the introduction of a variety of substituents at the thiophene 5-position. The 5-alkyl substituted and unsubstituted thiophenes were prepared using organolithium chemistry. Heteroatom substituents were introduced at the 5-position using a novel displacement reaction of 5-methylsulfonylthiophenes and the corresponding oxygen or sulfur anions. Small alkyl group substitution at the 5-position provided inhibitors equipotent with 3 but possessing improved solubility.

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ER -

Design and Synthesis of 4,5-disubstituted-thiophene-2-amidines as potent urokinase inhibitors

Abstract

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