VU0486846
(CAS: 1788055-12-8 )
Background Information of VU0486846
VU0486846 is a novel muscarinic acetylcholine receptor 1 (M1) positive allosteric modulator (PAM). M1 PAMs hold great promise for the treatment of cognitive impairment, schizophrenia, and Alzheimer’s disease.
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Chemical Information
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| 432.51 |
C25H28N4O3 |
1788055-12-8 |
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Structure Information of VU0486846
| Smiles |
C1C=C2O[[email protected]@H](C(N([[email protected]]3CCCC[[email protected]@H]3O)[H])=O)CN(CC3C=CC(N4N=CC=C4)=CC=3)C2=CC=1 |&1:4,7,12,r| |
| InChI |
InChI=1/C25H28N4O3/c30-22-8-3-1-6-20(22)27-25(31)24-17-28(21-7-2-4-9-23(21)32-24)16-18-10-12-19(13-11-18)29-15-5-14-26-29/h2,4-5,7,9-15,20,22,24,30H,1,3,6,8,16-17H2,(H,27,31)/t20-,22-,24+/s3 |
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Chemical and Physical Properties
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Reference
[1].Engers JL, et al. VU6007477, a Novel M1 PAM Based on a Pyrrolo[2,3-b]pyridine Carboxamide Core Devoid of Cholinergic Adverse Events. ACS Med Chem Lett. 2018 Sep 4;9(9):917-922.
Herein, we report the chemical optimization of a new series of M1 positive allosteric modulators (PAMs) based on a novel pyrrolo[2,3-b]pyridine core, developed via scaffold hopping and iterative parallel synthesis. The vast majority of analogs in this series proved to display robust cholinergic seizure activity. However, by removal of the secondary hydroxyl group, VU6007477 resulted with good rat M1 PAM potency (EC50 = 230 nM, 93% ACh max), minimal M1 agonist activity (agonist EC50 > 10 μM), good CNS penetration (rat brain/plasma K p = 0.28, K p,uu = 0.32; mouse K p = 0.16, K p,uu = 0.18), and no cholinergic adverse events (AEs, e.g., seizures). This work demonstrates that within a chemical series prone to robust M1 ago-PAM activity, SAR can result, which affords pure M1 PAMs, devoid of cholinergic toxicity/seizure liability.
