Rapid development of two factor IXa inhibitors from hit to lead

Dann L. Parker; Shawn Walsh; Bing Li; Esther Kim; Aurash Sharipour; Cameron Smith; Yi Heng Chen; Richard Berger; Bart Harper; Ting Zhang; Min Park; Min Shu; Jane Wu; Jiayi Xu; Sunita Dewnani; Edward C. Sherer; Alan Hruza; Paul Reichert; Wayne Geissler; Lisa Sonatore; Kenneth Ellsworth; James Balkovec; William Greenlee; Harold B. Wood

doi:10.1016/j.bmcl.2015.04.025

Rapid development of two factor IXa inhibitors from hit to lead

Dann L. Parker
, Shawn Walsh
, Bing Li
, Esther Kim
, Aurash Sharipour
, Cameron Smith
, Yi Heng Chen
, Richard Berger
, Bart Harper
, Ting Zhang
, Min Park
, Min Shu
, Jane Wu
, Jiayi Xu
, Sunita Dewnani
, Edward C. Sherer
, Alan Hruza
, Paul Reichert
, Wayne Geissler
, Lisa Sonatore

Kenneth Ellsworth, James Balkovec, William Greenlee, Harold B. Wood

Center for Discovery and Innovation

Merck

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

14 Scopus citations

Abstract

Abstract Two high-throughput screening hits were investigated for SAR against human factor IXa. Both hits feature a benzamide linked to a [6-5]-heteroaryl via an alkyl amine. In the case where this system is a benzimidazolyl-ethyl amine the binding potency for the hit was improved >500-fold, from 9 μM to 0.016 μM. For the other hit, which contains a tetrahydropyrido-indazole amine, potency was improved 20-fold, from 2 μM to 0.09 μM. X-ray crystal structures were obtained for an example of each class which improved understanding of the binding, and will enable further drug discovery efforts.

Original language	English
Article number	22608
Pages (from-to)	2321-2325
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	25
Issue number	11
DOIs	https://doi.org/10.1016/j.bmcl.2015.04.025
State	Published - 1 Jun 2015

Keywords

Anticoagulant
Factor IXa
Hit-to-lead
Parallel synthesis
Structure based drug design

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Parker, D. L., Walsh, S., Li, B., Kim, E., Sharipour, A., Smith, C., Chen, Y. H., Berger, R., Harper, B., Zhang, T., Park, M., Shu, M., Wu, J., Xu, J., Dewnani, S., Sherer, E. C., Hruza, A., Reichert, P., Geissler, W., ... Wood, H. B. (2015). Rapid development of two factor IXa inhibitors from hit to lead. Bioorganic and Medicinal Chemistry Letters, 25(11), 2321-2325. Article 22608. https://doi.org/10.1016/j.bmcl.2015.04.025

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title = "Rapid development of two factor IXa inhibitors from hit to lead",

abstract = "Abstract Two high-throughput screening hits were investigated for SAR against human factor IXa. Both hits feature a benzamide linked to a [6-5]-heteroaryl via an alkyl amine. In the case where this system is a benzimidazolyl-ethyl amine the binding potency for the hit was improved >500-fold, from 9 μM to 0.016 μM. For the other hit, which contains a tetrahydropyrido-indazole amine, potency was improved 20-fold, from 2 μM to 0.09 μM. X-ray crystal structures were obtained for an example of each class which improved understanding of the binding, and will enable further drug discovery efforts.",

keywords = "Anticoagulant, Factor IXa, Hit-to-lead, Parallel synthesis, Structure based drug design",

author = "Parker, \{Dann L.\} and Shawn Walsh and Bing Li and Esther Kim and Aurash Sharipour and Cameron Smith and Chen, \{Yi Heng\} and Richard Berger and Bart Harper and Ting Zhang and Min Park and Min Shu and Jane Wu and Jiayi Xu and Sunita Dewnani and Sherer, \{Edward C.\} and Alan Hruza and Paul Reichert and Wayne Geissler and Lisa Sonatore and Kenneth Ellsworth and James Balkovec and William Greenlee and Wood, \{Harold B.\}",

year = "2015",

month = jun,

day = "1",

doi = "10.1016/j.bmcl.2015.04.025",

language = "English",

volume = "25",

pages = "2321--2325",

journal = "Bioorganic and Medicinal Chemistry Letters",

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Parker, DL, Walsh, S, Li, B, Kim, E, Sharipour, A, Smith, C, Chen, YH, Berger, R, Harper, B, Zhang, T, Park, M, Shu, M, Wu, J, Xu, J, Dewnani, S, Sherer, EC, Hruza, A, Reichert, P, Geissler, W, Sonatore, L, Ellsworth, K, Balkovec, J, Greenlee, W & Wood, HB 2015, 'Rapid development of two factor IXa inhibitors from hit to lead', Bioorganic and Medicinal Chemistry Letters, vol. 25, no. 11, 22608, pp. 2321-2325. https://doi.org/10.1016/j.bmcl.2015.04.025

TY - JOUR

T1 - Rapid development of two factor IXa inhibitors from hit to lead

AU - Parker, Dann L.

AU - Walsh, Shawn

AU - Li, Bing

AU - Kim, Esther

AU - Sharipour, Aurash

AU - Smith, Cameron

AU - Chen, Yi Heng

AU - Berger, Richard

AU - Harper, Bart

AU - Zhang, Ting

AU - Park, Min

AU - Shu, Min

AU - Wu, Jane

AU - Xu, Jiayi

AU - Dewnani, Sunita

AU - Sherer, Edward C.

AU - Hruza, Alan

AU - Reichert, Paul

AU - Geissler, Wayne

AU - Sonatore, Lisa

AU - Ellsworth, Kenneth

AU - Balkovec, James

AU - Greenlee, William

AU - Wood, Harold B.

PY - 2015/6/1

Y1 - 2015/6/1

N2 - Abstract Two high-throughput screening hits were investigated for SAR against human factor IXa. Both hits feature a benzamide linked to a [6-5]-heteroaryl via an alkyl amine. In the case where this system is a benzimidazolyl-ethyl amine the binding potency for the hit was improved >500-fold, from 9 μM to 0.016 μM. For the other hit, which contains a tetrahydropyrido-indazole amine, potency was improved 20-fold, from 2 μM to 0.09 μM. X-ray crystal structures were obtained for an example of each class which improved understanding of the binding, and will enable further drug discovery efforts.

AB - Abstract Two high-throughput screening hits were investigated for SAR against human factor IXa. Both hits feature a benzamide linked to a [6-5]-heteroaryl via an alkyl amine. In the case where this system is a benzimidazolyl-ethyl amine the binding potency for the hit was improved >500-fold, from 9 μM to 0.016 μM. For the other hit, which contains a tetrahydropyrido-indazole amine, potency was improved 20-fold, from 2 μM to 0.09 μM. X-ray crystal structures were obtained for an example of each class which improved understanding of the binding, and will enable further drug discovery efforts.

KW - Anticoagulant

KW - Factor IXa

KW - Hit-to-lead

KW - Parallel synthesis

KW - Structure based drug design

UR - https://www.scopus.com/pages/publications/84937763524

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DO - 10.1016/j.bmcl.2015.04.025

M3 - Article

C2 - 25937013

AN - SCOPUS:84937763524

SN - 0960-894X

VL - 25

SP - 2321

EP - 2325

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 11

M1 - 22608

ER -

Rapid development of two factor IXa inhibitors from hit to lead

Abstract

Keywords

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