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. 2024 Sep 24;15(20):3744-3754.
doi: 10.1021/acschemneuro.4c00465. Online ahead of print.

Discovery of VU6016235: A Highly Selective, Orally Bioavailable, and Structurally Distinct Tricyclic M4 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator (PAM)

Julie L Engers  1   2 , Logan A Baker  1   2 , Sichen Chang  1   2 , Vincent B Luscombe  1   2 , Alice L Rodriguez  1   2 , Colleen M Niswender  1   2   3   4 , Hyekyung P Cho  1   2 , Michael Bubser  1   2 , Analisa Thompson Gray  1   2 , Carrie K Jones  1   2 , Weimin Peng  2 , Jerri M Rook  2 , 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   6 , Kayla J Temple  1   2
Affiliations

Discovery of VU6016235: A Highly Selective, Orally Bioavailable, and Structurally Distinct Tricyclic M4 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator (PAM)

Julie L Engers et al. ACS Chem Neurosci. .

Abstract

Herein, we report structure-activity relationship (SAR) studies to develop novel tricyclic M4 PAM scaffolds with improved pharmacological properties. This endeavor involved a "tie-back" strategy to replace a 5-amino-2,4-dimethylthieno[2,3-d]pyrimidine-6-carboxamide core, which led to the discovery of two novel tricyclic cores. While both tricyclic cores displayed low nanomolar potency against both human and rat M4 and were highly brain-penetrant, the 2,4-dimethylpyrido[4',3':4,5]thieno[2,3-d]pyrimidine tricycle core provided lead compound, VU6016235, with an overall superior pharmacological and drug metabolism and pharmacokinetics (DMPK) profile, as well as efficacy in a preclinical antipsychotic animal model.

Keywords: Alzheimer’s disease; Muscarinic acetylcholine receptor (mAChR); Muscarinic acetylcholine receptor subtype 4 (M4); Parkinson’s disease; Positive allosteric modulator (PAM); Schizophrenia; Structure−activity relationship (SAR).

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Conflict of interest statement

The authors declare the following competing financial interest(s): J.L.E., L.A.B., C.W.L., P.J.C., D.W.E., and K.J.T. are inventors on applications for composition of matter patents that protect several series of M4 positive allosteric modulators.

Figures

Figure 1
Figure 1
Structures of clinically advanced M4-targeting therapeutics.
Figure 2
Figure 2
Exploration of novel tricyclic cores as M4 PAMs revealed two unique M4 PAM tricyclic chemotypes: 7,9-dimethylthieno[2,3-d:4,5-d′]dipyrimidine core (5) and 2,4-dimethylpyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine core (6).
Scheme 1
Scheme 1. Synthesis of M4 PAM Analogues 14
Reagents and conditions: (a) 8, NH4SCN, 1,4-dioxane, 110 °C, 2 h, 46%; (b) 10, K2CO3, N-methyl-2-pyrrolidone (NMP), microwave-irradiated at 60 °C for 30 min, then microwave-irradiated at 100 °C for 1 h, 43%; (c) CH(OEt)3, 150 °C, 3 h, 99%; (d) POCl3, TEA, 1,2-dichloroethane (DCE), 110 °C, 3 h, 81%; (e) amine, N,N-diisopropylethylamine (DIEA), NMP, 60 °C for 2 h or microwave-irradiated at 100 °C for 10 min, 30–77%.
Scheme 2
Scheme 2. Synthesis of M4 PAM Analogues 22 and 23
Reagents and conditions: (a) 8, NH4SCN, 1,4-dioxane, 110 °C, 2 h, 21–42%; (b) 15, Na2CO3, DMF, 45 °C, 3 h, 52–91%; (c) CuBr2, tBuONO, acetonitrile (ACN), 1 h, 40–75%; (d) 18, Cs2CO3, Pd(dppf)Cl2, 1,4-dioxanes/H2O (10:1), 80 °C, 18 h, 44–76%; (e) (i) TFA, 120 °C, 2 h; (ii) NH4OH, 100 °C, 4.5 h, 30–88% over two steps; (f) POCl3, microwave-irradiated at 120 °C, 30 min, 13–92%; (g) aliphatic amine, DIEA or K2CO3, NMP, microwave-irradiated at 120–180 °C, 0.5–2 h, 8–20%; (h) benzyl amine, Pd2(dba)3, Xantphos, Cs2CO3, 1,4-dioxane, 110 °C, 6–18 h, 14–51%; (i) R2MgCl, Fe(acac)3, THF/NMP (5:1), 1–18 h, 31–41%.
Scheme 3
Scheme 3. Synthesis of M4 PAM Analogues 26, 27, and 28
Reagents and conditions: (a) N-chlorosuccinimide (NCS), DMF, 18 h, 55%; (b) POCl3, microwave-irradiated at 150 °C, 1 h, 45%; (c) pyrrolidine, DIEA, NMP, microwave-irradiated at 150 °C, 30 min, 15%; (d) 2-[4-(aminomethyl)phenyl]propan-2-ol, Pd2(dba)3, Xantphos, Cs2CO3, 1,4-dioxane, microwave-irradiated at 130 °C, 1 h, 29%; (e) cyclopropylboronic acid, Cs2CO3, Pd(dppf)Cl2, 1,4-dioxanes/H2O (10:1), microwave-irradiated at 110 °C, 30 min, 11%; (f) Zn0, Zn(CN)2, NiCl2, dppf, 4-(dimethylamino)pyridine (DMAP), ACN, 80 °C, 2 h, 43%.
Figure 3
Figure 3
VU6016235, administered orally, reverses amphetamine-induced hyperlocomotion in male Sprague–Dawley rats. (Left) Time course of locomotor activity. (Right) Total locomotor activity during the 60 min period following amphetamine administration. Data are means ± SEM of 6–8 animals per group. *p < 0.05, **p < 0.01,***p < 0.001 vs Vehicle + Amphetamine. VU0467154 = positive control. Vehicle = 10% Tween80 in H2O.
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