Optimization of the physicochemical and pharmacokinetic attributes in a 6-azauracil series of P2X 7 receptor antagonists leading to the discovery of the clinical candidate CE-224,535

Allen J. Duplantier; Mark A. Dombroski; Chakrapani Subramanyam; Aimee M. Beaulieu; Shang Poa Chang; Christopher A. Gabel; Crystal Jordan; Amit S. Kalgutkar; Kenneth G. Kraus; Jeff M. Labasi; Christopher Mussari; David G. Perregaux; Rick Shepard; Timothy J. Taylor; Kristen A. Trevena; Carrie Whitney-Pickett; Kwansik Yoon

doi:10.1016/j.bmcl.2011.04.077

Optimization of the physicochemical and pharmacokinetic attributes in a 6-azauracil series of P2X ₇ receptor antagonists leading to the discovery of the clinical candidate CE-224,535

Allen J. Duplantier, Mark A. Dombroski, Chakrapani Subramanyam, Aimee M. Beaulieu, Shang Poa Chang, Christopher A. Gabel, Crystal Jordan, Amit S. Kalgutkar, Kenneth G. Kraus, Jeff M. Labasi, Christopher Mussari, David G. Perregaux, Rick Shepard, Timothy J. Taylor, Kristen A. Trevena, Carrie Whitney-Pickett, Kwansik Yoon

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

60 Scopus citations

Abstract

High throughput screening (HTS) of our compound file provided an attractive lead compound with modest P2X ₇ receptor antagonist potency and high selectivity against a panel of receptors and channels, but also with high human plasma protein binding and a predicted short half-life in humans. Multi-parameter optimization was used to address the potency, physicochemical and pharmacokinetic properties which led to potent P2X ₇R antagonists with good disposition properties. Compound 33 (CE-224,535) was advanced to clinical studies for the treatment of rheumatoid arthritis.

Original language	English (US)
Pages (from-to)	3708-3711
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	21
Issue number	12
DOIs	https://doi.org/10.1016/j.bmcl.2011.04.077
State	Published - Jun 15 2011
Externally published	Yes

All Science Journal Classification (ASJC) codes

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

Keywords

6-Azauracil
Antagonist
Log P
P2X
Pharmacokinetic
Rheumatoid arthritis

Access to Document

10.1016/j.bmcl.2011.04.077

Cite this

Duplantier, A. J., Dombroski, M. A., Subramanyam, C., Beaulieu, A. M., Chang, S. P., Gabel, C. A., Jordan, C., Kalgutkar, A. S., Kraus, K. G., Labasi, J. M., Mussari, C., Perregaux, D. G., Shepard, R., Taylor, T. J., Trevena, K. A., Whitney-Pickett, C., & Yoon, K. (2011). Optimization of the physicochemical and pharmacokinetic attributes in a 6-azauracil series of P2X ₇ receptor antagonists leading to the discovery of the clinical candidate CE-224,535. Bioorganic and Medicinal Chemistry Letters, 21(12), 3708-3711. https://doi.org/10.1016/j.bmcl.2011.04.077

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title = "Optimization of the physicochemical and pharmacokinetic attributes in a 6-azauracil series of P2X 7 receptor antagonists leading to the discovery of the clinical candidate CE-224,535",

abstract = "High throughput screening (HTS) of our compound file provided an attractive lead compound with modest P2X 7 receptor antagonist potency and high selectivity against a panel of receptors and channels, but also with high human plasma protein binding and a predicted short half-life in humans. Multi-parameter optimization was used to address the potency, physicochemical and pharmacokinetic properties which led to potent P2X 7R antagonists with good disposition properties. Compound 33 (CE-224,535) was advanced to clinical studies for the treatment of rheumatoid arthritis.",

keywords = "6-Azauracil, Antagonist, Log P, P2X, Pharmacokinetic, Rheumatoid arthritis",

author = "Duplantier, {Allen J.} and Dombroski, {Mark A.} and Chakrapani Subramanyam and Beaulieu, {Aimee M.} and Chang, {Shang Poa} and Gabel, {Christopher A.} and Crystal Jordan and Kalgutkar, {Amit S.} and Kraus, {Kenneth G.} and Labasi, {Jeff M.} and Christopher Mussari and Perregaux, {David G.} and Rick Shepard and Taylor, {Timothy J.} and Trevena, {Kristen A.} and Carrie Whitney-Pickett and Kwansik Yoon",

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doi = "10.1016/j.bmcl.2011.04.077",

language = "English (US)",

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Duplantier, AJ, Dombroski, MA, Subramanyam, C, Beaulieu, AM, Chang, SP, Gabel, CA, Jordan, C, Kalgutkar, AS, Kraus, KG, Labasi, JM, Mussari, C, Perregaux, DG, Shepard, R, Taylor, TJ, Trevena, KA, Whitney-Pickett, C & Yoon, K 2011, 'Optimization of the physicochemical and pharmacokinetic attributes in a 6-azauracil series of P2X ₇ receptor antagonists leading to the discovery of the clinical candidate CE-224,535', Bioorganic and Medicinal Chemistry Letters, vol. 21, no. 12, pp. 3708-3711. https://doi.org/10.1016/j.bmcl.2011.04.077

Optimization of the physicochemical and pharmacokinetic attributes in a 6-azauracil series of P2X ₇ receptor antagonists leading to the discovery of the clinical candidate CE-224,535. / Duplantier, Allen J.; Dombroski, Mark A.; Subramanyam, Chakrapani et al.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 21, No. 12, 15.06.2011, p. 3708-3711.

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

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AU - Subramanyam, Chakrapani

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AU - Jordan, Crystal

AU - Kalgutkar, Amit S.

AU - Kraus, Kenneth G.

AU - Labasi, Jeff M.

AU - Mussari, Christopher

AU - Perregaux, David G.

AU - Shepard, Rick

AU - Taylor, Timothy J.

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AU - Yoon, Kwansik

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AB - High throughput screening (HTS) of our compound file provided an attractive lead compound with modest P2X 7 receptor antagonist potency and high selectivity against a panel of receptors and channels, but also with high human plasma protein binding and a predicted short half-life in humans. Multi-parameter optimization was used to address the potency, physicochemical and pharmacokinetic properties which led to potent P2X 7R antagonists with good disposition properties. Compound 33 (CE-224,535) was advanced to clinical studies for the treatment of rheumatoid arthritis.

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Duplantier AJ, Dombroski MA, Subramanyam C, Beaulieu AM, Chang SP, Gabel CA et al. Optimization of the physicochemical and pharmacokinetic attributes in a 6-azauracil series of P2X ₇ receptor antagonists leading to the discovery of the clinical candidate CE-224,535. Bioorganic and Medicinal Chemistry Letters. 2011 Jun 15;21(12):3708-3711. doi: 10.1016/j.bmcl.2011.04.077