Publication

Structure-kinetic relationships--an overlooked parameter in hit-to-lead optimization: a case of cyclopentylamines as chemokine receptor 2 antagonists

Vilums, M., Zweemer, A. J. M., Yu, Z., de Vries, H., Hillger, J. M., Wapenaar, H., Bollen, I. A. E., Barmare, F., Gross, R., Clemens, J., Krenitsky, P., Brussee, J., Stamos, D., Saunders, J., Heitman, L. H. & IJzerman, A. P., 10-Oct-2013, In : Journal of Medicinal Chemistry. 56, 19, p. 7706-7714 9 p.

Research output: Contribution to journalArticleAcademicpeer-review

APA

Vilums, M., Zweemer, A. J. M., Yu, Z., de Vries, H., Hillger, J. M., Wapenaar, H., ... IJzerman, A. P. (2013). Structure-kinetic relationships--an overlooked parameter in hit-to-lead optimization: a case of cyclopentylamines as chemokine receptor 2 antagonists. Journal of Medicinal Chemistry, 56(19), 7706-7714. https://doi.org/10.1021/jm4011737

Author

Vilums, Maris ; Zweemer, Annelien J. M. ; Yu, Zhiyi ; de Vries, Henk ; Hillger, Julia M. ; Wapenaar, Hannah ; Bollen, Ilse A. E. ; Barmare, Farhana ; Gross, Raymond ; Clemens, Jeremy ; Krenitsky, Paul ; Brussee, Johannes ; Stamos, Dean ; Saunders, John ; Heitman, Laura H. ; IJzerman, Adriaan P. / Structure-kinetic relationships--an overlooked parameter in hit-to-lead optimization : a case of cyclopentylamines as chemokine receptor 2 antagonists. In: Journal of Medicinal Chemistry. 2013 ; Vol. 56, No. 19. pp. 7706-7714.

Harvard

Vilums, M, Zweemer, AJM, Yu, Z, de Vries, H, Hillger, JM, Wapenaar, H, Bollen, IAE, Barmare, F, Gross, R, Clemens, J, Krenitsky, P, Brussee, J, Stamos, D, Saunders, J, Heitman, LH & IJzerman, AP 2013, 'Structure-kinetic relationships--an overlooked parameter in hit-to-lead optimization: a case of cyclopentylamines as chemokine receptor 2 antagonists', Journal of Medicinal Chemistry, vol. 56, no. 19, pp. 7706-7714. https://doi.org/10.1021/jm4011737

Standard

Structure-kinetic relationships--an overlooked parameter in hit-to-lead optimization : a case of cyclopentylamines as chemokine receptor 2 antagonists. / Vilums, Maris; Zweemer, Annelien J. M.; Yu, Zhiyi; de Vries, Henk; Hillger, Julia M.; Wapenaar, Hannah; Bollen, Ilse A. E.; Barmare, Farhana; Gross, Raymond; Clemens, Jeremy; Krenitsky, Paul; Brussee, Johannes; Stamos, Dean; Saunders, John; Heitman, Laura H.; IJzerman, Adriaan P.

In: Journal of Medicinal Chemistry, Vol. 56, No. 19, 10.10.2013, p. 7706-7714.

Research output: Contribution to journalArticleAcademicpeer-review

Vancouver

Vilums M, Zweemer AJM, Yu Z, de Vries H, Hillger JM, Wapenaar H et al. Structure-kinetic relationships--an overlooked parameter in hit-to-lead optimization: a case of cyclopentylamines as chemokine receptor 2 antagonists. Journal of Medicinal Chemistry. 2013 Oct 10;56(19):7706-7714. https://doi.org/10.1021/jm4011737


BibTeX

@article{a55b2837e54d468fb0352e528fe109c6,
title = "Structure-kinetic relationships--an overlooked parameter in hit-to-lead optimization: a case of cyclopentylamines as chemokine receptor 2 antagonists",
abstract = "Preclinical models of inflammatory diseases (e.g., neuropathic pain, rheumatoid arthritis, and multiple sclerosis) have pointed to a critical role of the chemokine receptor 2 (CCR2) and chemokine ligand 2 (CCL2). However, one of the biggest problems of high-affinity inhibitors of CCR2 is their lack of efficacy in clinical trials. We report a new approach for the design of high-affinity and long-residence-time CCR2 antagonists. We developed a new competition association assay for CCR2, which allows us to investigate the relation of the structure of the ligand and its receptor residence time [i.e., structure-kinetic relationship (SKR)] next to a traditional structure-affinity relationship (SAR). By applying combined knowledge of SAR and SKR, we were able to re-evaluate the hit-to-lead process of cyclopentylamines as CCR2 antagonists. Affinity-based optimization yielded compound 1 with good binding (Ki = 6.8 nM) but very short residence time (2.4 min). However, when the optimization was also based on residence time, the hit-to-lead process yielded compound 22a, a new high-affinity CCR2 antagonist (3.6 nM), with a residence time of 135 min.",
keywords = "CCR2 ANTAGONISTS, PHARMACOLOGICAL CHARACTERIZATION, BINDING-KINETICS, DISCOVERY, ASSOCIATION, MECHANISMS, INCB3344, DRUGS, MCP-1, MICE",
author = "Maris Vilums and Zweemer, {Annelien J. M.} and Zhiyi Yu and {de Vries}, Henk and Hillger, {Julia M.} and Hannah Wapenaar and Bollen, {Ilse A. E.} and Farhana Barmare and Raymond Gross and Jeremy Clemens and Paul Krenitsky and Johannes Brussee and Dean Stamos and John Saunders and Heitman, {Laura H.} and IJzerman, {Adriaan P.}",
year = "2013",
month = "10",
day = "10",
doi = "10.1021/jm4011737",
language = "English",
volume = "56",
pages = "7706--7714",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "AMER CHEMICAL SOC",
number = "19",

}

RIS

TY - JOUR

T1 - Structure-kinetic relationships--an overlooked parameter in hit-to-lead optimization

T2 - a case of cyclopentylamines as chemokine receptor 2 antagonists

AU - Vilums, Maris

AU - Zweemer, Annelien J. M.

AU - Yu, Zhiyi

AU - de Vries, Henk

AU - Hillger, Julia M.

AU - Wapenaar, Hannah

AU - Bollen, Ilse A. E.

AU - Barmare, Farhana

AU - Gross, Raymond

AU - Clemens, Jeremy

AU - Krenitsky, Paul

AU - Brussee, Johannes

AU - Stamos, Dean

AU - Saunders, John

AU - Heitman, Laura H.

AU - IJzerman, Adriaan P.

PY - 2013/10/10

Y1 - 2013/10/10

N2 - Preclinical models of inflammatory diseases (e.g., neuropathic pain, rheumatoid arthritis, and multiple sclerosis) have pointed to a critical role of the chemokine receptor 2 (CCR2) and chemokine ligand 2 (CCL2). However, one of the biggest problems of high-affinity inhibitors of CCR2 is their lack of efficacy in clinical trials. We report a new approach for the design of high-affinity and long-residence-time CCR2 antagonists. We developed a new competition association assay for CCR2, which allows us to investigate the relation of the structure of the ligand and its receptor residence time [i.e., structure-kinetic relationship (SKR)] next to a traditional structure-affinity relationship (SAR). By applying combined knowledge of SAR and SKR, we were able to re-evaluate the hit-to-lead process of cyclopentylamines as CCR2 antagonists. Affinity-based optimization yielded compound 1 with good binding (Ki = 6.8 nM) but very short residence time (2.4 min). However, when the optimization was also based on residence time, the hit-to-lead process yielded compound 22a, a new high-affinity CCR2 antagonist (3.6 nM), with a residence time of 135 min.

AB - Preclinical models of inflammatory diseases (e.g., neuropathic pain, rheumatoid arthritis, and multiple sclerosis) have pointed to a critical role of the chemokine receptor 2 (CCR2) and chemokine ligand 2 (CCL2). However, one of the biggest problems of high-affinity inhibitors of CCR2 is their lack of efficacy in clinical trials. We report a new approach for the design of high-affinity and long-residence-time CCR2 antagonists. We developed a new competition association assay for CCR2, which allows us to investigate the relation of the structure of the ligand and its receptor residence time [i.e., structure-kinetic relationship (SKR)] next to a traditional structure-affinity relationship (SAR). By applying combined knowledge of SAR and SKR, we were able to re-evaluate the hit-to-lead process of cyclopentylamines as CCR2 antagonists. Affinity-based optimization yielded compound 1 with good binding (Ki = 6.8 nM) but very short residence time (2.4 min). However, when the optimization was also based on residence time, the hit-to-lead process yielded compound 22a, a new high-affinity CCR2 antagonist (3.6 nM), with a residence time of 135 min.

KW - CCR2 ANTAGONISTS

KW - PHARMACOLOGICAL CHARACTERIZATION

KW - BINDING-KINETICS

KW - DISCOVERY

KW - ASSOCIATION

KW - MECHANISMS

KW - INCB3344

KW - DRUGS

KW - MCP-1

KW - MICE

U2 - 10.1021/jm4011737

DO - 10.1021/jm4011737

M3 - Article

C2 - 24028535

VL - 56

SP - 7706

EP - 7714

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 19

ER -

ID: 20935860