Chemical lead optimization of a pan Gq mAChR M1, M3, M5 positive allosteric modulator (PAM) lead. Part II: development of a potent and highly selective M1 PAM

Thomas M Bridges; J Phillip Kennedy; Meredith J Noetzel; Micah L Breininger; Patrick R Gentry; P Jeffrey Conn; Craig W Lindsley

doi:10.1016/j.bmcl.2010.01.109

Chemical lead optimization of a pan Gq mAChR M1, M3, M5 positive allosteric modulator (PAM) lead. Part II: development of a potent and highly selective M1 PAM

Thomas M Bridges, J Phillip Kennedy, Meredith J Noetzel, Micah L Breininger, Patrick R Gentry, P Jeffrey Conn, Craig W Lindsley

48 Citations (Scopus)

Abstract

This Letter describes a chemical lead optimization campaign directed at VU0119498, a pan G_q mAChR M₁, M₃, M₅ positive allosteric modulator (PAM) with the goal of developing a selective M₁ PAM. An iterative library synthesis approach delivered a potent (M₁ EC₅₀ = 830 nM) and highly selective M₁ PAM (>30 μM vs M₂-M₅).

Original language	English
Journal	Bioorganic & Medicinal Chemistry Letters
Volume	20
Issue number	6
Pages (from-to)	1972-5
Number of pages	4
ISSN	0960-894X
DOIs	https://doi.org/10.1016/j.bmcl.2010.01.109
Publication status	Published - 15 Mar 2010
Externally published	Yes

Keywords

Allosteric Regulation
Cholinergic Agents/chemistry
Drug Design
Receptors, Muscarinic/drug effects
Structure-Activity Relationship

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10.1016/j.bmcl.2010.01.109

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Bridges, T. M., Phillip Kennedy, J., Noetzel, M. J., Breininger, M. L., Gentry, P. R., Conn, P. J., & Lindsley, C. W. (2010). Chemical lead optimization of a pan Gq mAChR M1, M3, M5 positive allosteric modulator (PAM) lead. Part II: development of a potent and highly selective M1 PAM. Bioorganic & Medicinal Chemistry Letters, 20(6), 1972-5. https://doi.org/10.1016/j.bmcl.2010.01.109

Chemical lead optimization of a pan Gq mAChR M1, M3, M5 positive allosteric modulator (PAM) lead. Part II : development of a potent and highly selective M1 PAM. / Bridges, Thomas M; Phillip Kennedy, J; Noetzel, Meredith J et al.

In: Bioorganic & Medicinal Chemistry Letters, Vol. 20, No. 6, 15.03.2010, p. 1972-5.

Research output: Contribution to journal › Journal article › Research › peer-review

Bridges, TM, Phillip Kennedy, J, Noetzel, MJ, Breininger, ML, Gentry, PR, Conn, PJ & Lindsley, CW 2010, 'Chemical lead optimization of a pan Gq mAChR M1, M3, M5 positive allosteric modulator (PAM) lead. Part II: development of a potent and highly selective M1 PAM', Bioorganic & Medicinal Chemistry Letters, vol. 20, no. 6, pp. 1972-5. https://doi.org/10.1016/j.bmcl.2010.01.109

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abstract = "This Letter describes a chemical lead optimization campaign directed at VU0119498, a pan Gq mAChR M1, M3, M5 positive allosteric modulator (PAM) with the goal of developing a selective M1 PAM. An iterative library synthesis approach delivered a potent (M1 EC50 = 830 nM) and highly selective M1 PAM (>30 μM vs M2-M5).",

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KW - Drug Design

KW - Receptors, Muscarinic/drug effects

KW - Structure-Activity Relationship

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Chemical lead optimization of a pan Gq mAChR M1, M3, M5 positive allosteric modulator (PAM) lead. Part II: development of a potent and highly selective M1 PAM

Abstract

Keywords

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