Discovery of VU6008677: A Structurally Distinct Tricyclic M4 Positive Allosteric Modulator with Improved CYP450 Profile

Rory A Capstick; Sean R Bollinger; Julie L Engers; Madeline F Long; Sichen Chang; Vincent B Luscombe; Alice L Rodriguez; Colleen M Niswender; Thomas M Bridges; Olivier Boutaud; P Jeffrey Conn; Darren W Engers; Craig W Lindsley; Kayla J Temple

doi:10.1021/acsmedchemlett.4c00249

Discovery of VU6008677: A Structurally Distinct Tricyclic M₄ Positive Allosteric Modulator with Improved CYP450 Profile

ACS Med Chem Lett. 2024 Jul 3;15(8):1358-1366. doi: 10.1021/acsmedchemlett.4c00249. eCollection 2024 Aug 8.

Authors

Rory A Capstick^{1

2}, Sean R Bollinger^{1

2}, Julie L Engers^{1

2}, Madeline F Long^{1

2}, Sichen Chang^{1

2}, Vincent B Luscombe^{1

2}, Alice L Rodriguez^{1

2}, Colleen M Niswender^{1

2

3

4}, Thomas M Bridges^{1

2}, Olivier Boutaud^{1

2}, P Jeffrey Conn^{1

2

3}, Darren W Engers^{1

2}, Craig W Lindsley^{1

2

5}, Kayla J Temple^{1

2}

Affiliations

¹ Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.
² Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
³ Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
⁴ Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
⁵ Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.

Abstract

This Letter details our efforts to develop novel tricyclic muscarinic acetylcholine receptor subtype 4 (M₄) positive allosteric modulator (PAM) scaffolds with improved pharmacological properties. This endeavor involved a "tie-back" strategy to replace the 3-amino-5-chloro-4,6-dimethylthieno[2,3-b]pyridine-2-carboxamide core, which led to the discovery of two novel tricyclic cores: an 8-chloro-9-methylpyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amine core and 8-chloro-7,9-dimethylpyrido[3',2':4,5]furo[3,2-d]pyrimidin-4-amine core. Both tricyclic cores displayed low nanomolar potency against human M₄ and greatly reduced cytochrome P450 inhibition when compared with parent compound ML253.

Abstract

Grants and funding