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. 2016 Dec 16;8(2):233-238.
doi: 10.1021/acsmedchemlett.6b00461. eCollection 2017 Feb 9.

Discovery of VU0467485/AZ13713945: An M4 PAM Evaluated as a Preclinical Candidate for the Treatment of Schizophrenia

Michael R Wood  1 , Meredith J Noetzel  1 , Bruce J Melancon  1 , Michael S Poslusney  2 , Kellie D Nance  2 , Miguel A Hurtado  2 , Vincent B Luscombe  1 , Rebecca L Weiner  1 , Alice L Rodriguez  1 , Atin Lamsal  1 , Sichen Chang  1 , Michael Bubser  1 , Anna L Blobaum  1 , Darren W Engers  1 , Colleen M Niswender  3 , Carrie K Jones  3 , Nicholas J Brandon  4 , Michael W Wood  4 , Mark E Duggan  4 , P Jeffrey Conn  3 , Thomas M Bridges  1 , Craig W Lindsley  1
Affiliations

Discovery of VU0467485/AZ13713945: An M4 PAM Evaluated as a Preclinical Candidate for the Treatment of Schizophrenia

Michael R Wood et al. ACS Med Chem Lett. .

Abstract

Herein, we report the structure-activity relationships within a series of potent, selective, and orally bioavailable muscarinic acetylcholine receptor 4 (M4) positive allosteric modulators (PAMs). Compound 6c (VU0467485) possesses robust in vitro M4 PAM potency across species and in vivo efficacy in preclinical models of schizophrenia. Coupled with an attractive DMPK profile and suitable predicted human PK, 6c (VU0467485) was evaluated as a preclinical development candidate.

Keywords: Positive allosteric modulator (PAM); VU0467485; muscarinic acetylcholine receptor 4 (M4); schizophrenia.

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Conflict of interest statement

The authors declare the following competing financial interest(s): The authors are developing M4 PAMs for the treatment of schizophrenia and hold patents on the same.

Figures

Figure 1
Figure 1
Structures of reported M4 PAMs. LY2033298 (1) was the first reported M4 PAM but was human-preferring in potency. VU0152100 (2) was the first centrally active M4 PAM in rodents, and VU0467154 (3) has proven to be the best-in-class M4 PAM rodent in vivo tool compound.
Scheme 1
Scheme 1. Synthesis of Analogues 6
Reagents and conditions: (a) methyl thioglycolate, MeOH, 1 M aq. NaOH, 150 °C, microwave, 30 min, 78%; (b) NH2CH2Ar(Het), HATU, DMF, DIEPA, 2 h, 45–92%.
Figure 2
Figure 2
Molecular pharmacology profile of M4 PAM 6c. (A) Enhanced intracellular calcium release induced by a subthreshold concentration of acetylcholine (EC20), a PAM CRC on both rat and human M4, with EC50s of 26.6 and 78.8 nM, respectively. (B) Compound 6c induces a ∼45-fold maximal leftward shift of the hM4 acetylcholine response curve at 10 μM. (C) Compound 6c is highly selective for hM4 over hM1–3,5. (D) Compound 6c is highly selective for rM4 over rM1–3,5. Data represent means from at least three independent determinations performed in triplicate using CHO cells stably transfected with the indicated mAChR.
Figure 3
Figure 3
Metabolite identification studies for 6c across species (rat, dog, cyno monkey, and human).
Figure 4
Figure 4
P450 phenotyping and CYP mapping for 6c, indicating that multiple CYP450s (3A4/2C19/1A2 and to a lesser extent, 2C9) catalyze biotransformation.
Figure 5
Figure 5
Compound 6c has antipsychotic-like activity in an AHL rat model. Compound 6c dose-dependently (1–10 mg/kg, po) reverses AHL (amphetamine, 0.75 mg/kg, s.c., *p < 0.05 vs vehicle + amphetamine, **p < 0.01 vs vehicle + amphetamine, ***p < 0.001 vs vehicle + amphetamine). N = 6–8 rats/group.
Figure 6
Figure 6
Compound 6c has antipsychotic-like activity in an MK-801 hyperlocomotion rat model. Compound 6c dose-dependently (10−30 mg/kg, po) reverses MK-801-induced hyperlocomtion (MK-801, 0.18 mg/kg, s.c., *p < 0.05 vs vehicle + MK-801. N = 6−8 rats /group.
See this image and copyright information in PMC

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