Design and Identification of a Novel, Functionally Subtype Selective GABAA Positive Allosteric Modulator (PF-06372865)

被引：32

作者：

Owen, Robert M. ^{[2
]}

Blakemore, David ^{[2
]}

Cao, Lishuan ^{[3
]}

Flanagan, Neil ^{[5
]}

Fish, Rebecca ^{[3
]}

Gibson, Karl R. ^{[6
]}

Gurrell, Rachel ^{[3
]}

Huh, Chan Woo ^{[7
]}

Kammonen, Juha ^{[3
,14
]}

Mortimer-Cassen, Elisabeth ^{[4
,13
]}

Nickolls, Sarah A. ^{[3
,11
]}

Omoto, Kiyoyuki ^{[2
]}

Owen, Dafydd ^{[7
]}

Pike, Andy ^{[1
,9
]}

Pryde, David C. ^{[2
,3
,10
]}

Reynolds, David S.

Roeloffs, Rosemarie ^{[8
,12
]}

Rose, Colin ^{[7
]}

Stead, Clara ^{[3
]}

Takeuchi, Mifune ^{[6
]}

Warmus, Joseph S. ^{[7
]}

Watson, Christine ^{[6
]}

机构：

[1] Pfizer Ltd, Pharmacokinet Dynam & Metab, Portway,Granta Pk, Cambridge CB21 6GS, England

[2] Pfizer Ltd, Worldwide Med Chem, Portway,Granta Pk, Cambridge CB21 6GS, England

[3] Pfizer Ltd, Pfizer Neusentis, Portway,Granta Pk, Cambridge CB21 6GS, England

[4] Pfizer Ltd, Global Safety Grp, Portway,Granta Pk, Cambridge CB21 6GS, England

[5] Pfizer Ltd, Pharmaceut Sci, Portway,Granta Pk, Cambridge CB21 6GS, England

[6] Pfizer Global Res & Dev, Worldwide Med Chem Sandwich Labs, Ramsgate Rd, Sandwich CT13 9NJ, Kent, England

[7] Pfizer Global Res & Dev, Worldwide Med Chem, S58 Eastern Point Rd, Groton, CT 06340 USA

[8] Pfizer Icagen, Res Triangle Pk, NC 27703 USA

[9] AstraZeneca, IMED Biotech Unit, Oncol, DMPK, Cambridge, England

[10] Curadev Pharma Ltd, Discovery Pk House,Ramsgate Rd, Sandwich CT13 9ND, Kent, England

[11] GSK Med Res Ctr, Gunnels Wood Rd, Stevenage SG1 2NY, Herts, England

[12] Axovant Sci Inc, 324 Blackwell St,Suite 1220, Durham, NC 27701 USA

[13] AstraZeneca, BioPharmaceut R&D, Clin Pharmacol & Safety Sci, Cambridge, England

[14] Charles River, Chesterford Res Pk, Cambridge CB10 1XL, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2019年 / 62卷 / 12期

关键词：

CENTRAL-NERVOUS-SYSTEM; MULTIPARAMETER OPTIMIZATION; AGONIST; LORAZEPAM; BENZODIAZEPINES; PHARMACOLOGY; RECEPTORS; DISCOVERY; EFFICACY; MK-0343;

D O I：

10.1021/acs.jmedchem.9b00322

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 and functional activity. As designing in the desired level of functional selectivity proved difficult, a probability-based assessment was performed to focus the project's efforts on a single subseries that had the greatest odds of delivering the target profile. These efforts ultimately led to the identification of two precandidates from this subseries, which were advanced to preclinical safety studies and subsequently to the identification of the clinical candidate PF-06372865.

引用

页码：5773 / 5796

页数：24