Design and identification of a novel, functionally subtype selective GABA A positive allosteric modulator (PF-06372865)

• Published in: Journal of medicinal chemistry Vol. 62; no. 12; pp. 5773 - 5796
• Main Authors: Owen, Robert M., Blakemore, David C, Cao, Lishuang, Flanagan, Neil, Fish, Rebecca, Gibson, Karl R, Gurrell, Rachel, Huh, Chan Woo, Kammonen, Juha, Mortimer-Cassen, Elisabeth, Nickolls, Sarah, Omoto, Kiyoyuki, Owen, Dafydd R, Pike, Andrew, Pryde, David C., Reynolds, David, Roeloffs, Rosemarie, Rose, Colin R., Stead, Clara, Takeuchi, Mifune, Warmus, Joseph S, Watson, Christine
• Format: Journal Article
• Language: English
• Published: WASHINGTON Amer Chemical Soc 27.06.2019
• Subjects: Allosteric Regulation - drug effects; Chemistry, Medicinal; Drug Design; Humans; Imidazoles - chemistry; Imidazoles - pharmacology; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Pyridazines - chemistry; Pyridazines - pharmacology; Receptors, GABA-A - metabolism; Science & Technology; LORAZEPAM; EFFICACY; PHARMACOLOGY; CENTRAL-NERVOUS-SYSTEM; BENZODIAZEPINES; RECEPTORS; MULTIPARAMETER OPTIMIZATION; MK-0343; DISCOVERY; AGONIST

The design, optimization, and evaluation of a series of novel imidazopyridazine-based subtype-selective positive allosteric modulators (PAMs) for the GABA(A) ligand-gated ion channel are described. From a set of initial hits multiple subseries were designed and evaluated based on binding affinity an...