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Discovery of N-(4-methoxy-7-methylbenzo[d]thiazol-2-yl)isonicatinamide, ML293, as a novel, selective and brain penetrant positive allosteric modulator of the muscarinic 4 (M4) receptor
- Source :
- Bioorganicmedicinal chemistry letters. 22(15)
- Publication Year :
- 2012
-
Abstract
- Herein we describe the discovery and development of a novel class of M4 positive allosteric modulators, culminating in the discovery of ML293. ML293 exhibited modest potency at the human M4 receptor (EC50 = 1.3 μM) and excellent efficacy as noted by the 14.6-fold leftward shift of the agonist concentration–response curve. ML293 was also selective versus the other muscarinic subtypes and displayed excellent in vivo PK properties in rat with low IV clearance (11.6 mL/min/kg) and excellent brain exposure (PO PBL, 10 mg/kg at 1 h, [Brain] = 10.3 μM, B:P = 0.85).
- Subjects :
- Agonist
Niacinamide
Allosteric modulator
Stereochemistry
medicine.drug_class
Clinical Biochemistry
Allosteric regulation
education
Drug Evaluation, Preclinical
Pharmaceutical Science
CHO Cells
Pharmacology
Biochemistry
Article
Structure-Activity Relationship
Cricetulus
Allosteric Regulation
In vivo
Cricetinae
Drug Discovery
Muscarinic acetylcholine receptor
medicine
Potency
Structure–activity relationship
Animals
Humans
Receptor
Molecular Biology
Receptor, Muscarinic M4
Chemistry
Organic Chemistry
Brain
Amides
Rats
Molecular Medicine
Subjects
Details
- ISSN :
- 14643405
- Volume :
- 22
- Issue :
- 15
- Database :
- OpenAIRE
- Journal :
- Bioorganicmedicinal chemistry letters
- Accession number :
- edsair.doi.dedup.....ca7074275b7ff3861b07b46e021eba93