3-Substituted Quinolines as RORγt Inverse Agonists

Virginia M. Tanis; Hariharan Venkatesan; Maxwell D. Cummings; Michael Albers; J. Kent Barbay; Krystal Herman; David A. Kummer; Cynthia Milligan; Marina I. Nelen; Rachel Nishimura; Thomas Schlueter; Brian Scott; John Spurlino; Ronald Wolin; Craig Woods; Xiaohua Xue; James P. Edwards; Anne M. Fourie; Kristi Leonard

doi:10.1016/j.bmcl.2019.04.021

3-Substituted Quinolines as RORγt Inverse Agonists

Virginia M. Tanis, Hariharan Venkatesan, Maxwell D. Cummings, Michael Albers, J. Kent Barbay, Krystal Herman, David A. Kummer, Cynthia Milligan, Marina I. Nelen, Rachel Nishimura, Thomas Schlueter, Brian Scott, John Spurlino, Ronald Wolin, Craig Woods, Xiaohua Xue, James P. Edwards, Anne M. Fourie, Kristi Leonard

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

10 Scopus citations

Abstract

We have previously reported the syntheses of a series of 3,6-disubstituted quinolines as modulators of the retinoic acid receptor-related orphan receptor gamma t (RORγt). These molecules are potent binders but are high molecular weight and they exhibited poor solubility at pH 2 and pH 7. This manuscript details our efforts at improving physical chemical properties for this series of compounds by increasing the diversity at the 3-position (i.e. introducing heteroatoms and lowering the molecular weight). These efforts have led to molecules which are potent binders with improved solubility.

Original language	English (US)
Pages (from-to)	1463-1470
Number of pages	8
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	29
Issue number	12
DOIs	https://doi.org/10.1016/j.bmcl.2019.04.021
State	Published - Jun 15 2019
Externally published	Yes

Keywords

IL-17
Inverse agonist
RORγt
Retinoic acid-related orphan nuclear receptor gamma t
Th17

ASJC Scopus subject areas

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

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10.1016/j.bmcl.2019.04.021

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Tanis, V. M., Venkatesan, H., Cummings, M. D., Albers, M., Kent Barbay, J., Herman, K., Kummer, D. A., Milligan, C., Nelen, M. I., Nishimura, R., Schlueter, T., Scott, B., Spurlino, J., Wolin, R., Woods, C., Xue, X., Edwards, J. P., Fourie, A. M., & Leonard, K. (2019). 3-Substituted Quinolines as RORγt Inverse Agonists. Bioorganic and Medicinal Chemistry Letters, 29(12), 1463-1470. https://doi.org/10.1016/j.bmcl.2019.04.021

Tanis, VM, Venkatesan, H, Cummings, MD, Albers, M, Kent Barbay, J, Herman, K, Kummer, DA, Milligan, C, Nelen, MI, Nishimura, R, Schlueter, T, Scott, B, Spurlino, J, Wolin, R, Woods, C, Xue, X, Edwards, JP, Fourie, AM & Leonard, K 2019, '3-Substituted Quinolines as RORγt Inverse Agonists', Bioorganic and Medicinal Chemistry Letters, vol. 29, no. 12, pp. 1463-1470. https://doi.org/10.1016/j.bmcl.2019.04.021

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abstract = "We have previously reported the syntheses of a series of 3,6-disubstituted quinolines as modulators of the retinoic acid receptor-related orphan receptor gamma t (RORγt). These molecules are potent binders but are high molecular weight and they exhibited poor solubility at pH 2 and pH 7. This manuscript details our efforts at improving physical chemical properties for this series of compounds by increasing the diversity at the 3-position (i.e. introducing heteroatoms and lowering the molecular weight). These efforts have led to molecules which are potent binders with improved solubility.",

keywords = "IL-17, Inverse agonist, RORγt, Retinoic acid-related orphan nuclear receptor gamma t, Th17",

author = "Tanis, {Virginia M.} and Hariharan Venkatesan and Cummings, {Maxwell D.} and Michael Albers and {Kent Barbay}, J. and Krystal Herman and Kummer, {David A.} and Cynthia Milligan and Nelen, {Marina I.} and Rachel Nishimura and Thomas Schlueter and Brian Scott and John Spurlino and Ronald Wolin and Craig Woods and Xiaohua Xue and Edwards, {James P.} and Fourie, {Anne M.} and Kristi Leonard",

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AU - Tanis, Virginia M.

AU - Venkatesan, Hariharan

AU - Cummings, Maxwell D.

AU - Albers, Michael

AU - Kent Barbay, J.

AU - Herman, Krystal

AU - Kummer, David A.

AU - Milligan, Cynthia

AU - Nelen, Marina I.

AU - Nishimura, Rachel

AU - Schlueter, Thomas

AU - Scott, Brian

AU - Spurlino, John

AU - Wolin, Ronald

AU - Woods, Craig

AU - Xue, Xiaohua

AU - Edwards, James P.

AU - Fourie, Anne M.

AU - Leonard, Kristi

PY - 2019/6/15

Y1 - 2019/6/15

N2 - We have previously reported the syntheses of a series of 3,6-disubstituted quinolines as modulators of the retinoic acid receptor-related orphan receptor gamma t (RORγt). These molecules are potent binders but are high molecular weight and they exhibited poor solubility at pH 2 and pH 7. This manuscript details our efforts at improving physical chemical properties for this series of compounds by increasing the diversity at the 3-position (i.e. introducing heteroatoms and lowering the molecular weight). These efforts have led to molecules which are potent binders with improved solubility.

AB - We have previously reported the syntheses of a series of 3,6-disubstituted quinolines as modulators of the retinoic acid receptor-related orphan receptor gamma t (RORγt). These molecules are potent binders but are high molecular weight and they exhibited poor solubility at pH 2 and pH 7. This manuscript details our efforts at improving physical chemical properties for this series of compounds by increasing the diversity at the 3-position (i.e. introducing heteroatoms and lowering the molecular weight). These efforts have led to molecules which are potent binders with improved solubility.

KW - IL-17

KW - Inverse agonist

KW - RORγt

KW - Retinoic acid-related orphan nuclear receptor gamma t

KW - Th17

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ER -

3-Substituted Quinolines as RORγt Inverse Agonists

Abstract

Keywords

ASJC Scopus subject areas

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