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Challenges in the development of an M4 PAM preclinical candidate: The discovery, SAR, and in vivo characterization of a series of 3-aminoazetidine-derived amides.
- Source :
-
Bioorganic & Medicinal Chemistry Letters . Jul2017, Vol. 27 Issue 13, p2990-2995. 6p. - Publication Year :
- 2017
-
Abstract
- This letter details the continued chemical optimization of a novel series of M 4 positive allosteric modulators (PAMs) based on a 5-amino-thieno[2,3- c ]pyridazine core by incorporating a 3-amino azetidine amide moiety. The analogs described within this work represent the most potent M 4 PAMs reported for this series to date. The SAR to address potency, clearance, subtype selectivity, CNS exposure, and P-gp efflux are described. This work culminated in the discovery of VU6000918, which demonstrated robust efficacy in a rat amphetamine-induced hyperlocomotion reversal model at a minimum efficacious dose of 0.3 mg/kg. [ABSTRACT FROM AUTHOR]
- Subjects :
- *AMIDES
*ALLOSTERIC regulation
*PYRIDAZINES
*AMPHETAMINES
*SCHIZOPHRENIA treatment
Subjects
Details
- Language :
- English
- ISSN :
- 0960894X
- Volume :
- 27
- Issue :
- 13
- Database :
- Academic Search Index
- Journal :
- Bioorganic & Medicinal Chemistry Letters
- Publication Type :
- Academic Journal
- Accession number :
- 123258352
- Full Text :
- https://doi.org/10.1016/j.bmcl.2017.05.014