Development of a Highly Potent, Novel M5Positive Allosteric Modulator (PAM) Demonstrating CNS Exposure: 1-((1H-Indazol-5-yl)sulfoneyl)-N-ethyl-N-(2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (ML380) | Zendy

Patrick R. Gentry | Zendy; Masaya Kokubo | Zendy; Thomas M. Bridges | Zendy; Meredith J. Noetzel | Zendy; Hyekyung P. Cho | Zendy; Atin Lamsal | Zendy; Emery Smith | Zendy; Peter Chase | Zendy; Peter Hodder | Zendy; Colleen M. Niswender | Zendy; J. Scott Daniels | Zendy; P. Jeffrey Conn | Zendy; Craig W. Lindsley | Zendy; Michael R. Wood | Zendy

Open Access

Development of a Highly Potent, Novel M₅Positive Allosteric Modulator (PAM) Demonstrating CNS Exposure: 1-((1H-Indazol-5-yl)sulfoneyl)-N-ethyl-N-(2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (ML380)

Author(s) -

Patrick R. Gentry,

Masaya Kokubo,

Thomas M. Bridges,

Meredith J. Noetzel,

Hyekyung P. Cho,

Atin Lamsal,

Emery Smith,

Peter Chase,

Peter Hodder,

Colleen M. Niswender,

J. Scott Daniels,

P. Jeffrey Conn,

Craig W. Lindsley,

Michael R. Wood

Publication year - 2014

Publication title -

journal of medicinal chemistry

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 2.01

H-Index - 261

eISSN - 1520-4804

pISSN - 0022-2623

DOI - 10.1021/jm500995y

Subject(s) - chemistry , allosteric regulation , muscarinic acetylcholine receptor , allosteric modulator , potency , ec50 , pharmacology , chemotype , stereochemistry , in vitro , receptor , combinatorial chemistry , biochemistry , chromatography , medicine , essential oil

A functional high throughput screen identified a novel chemotype for the positive allosteric modulation (PAM) of the muscarinic acetylcholine receptor (mAChR) subtype 5 (M5). Application of rapid analog, iterative parallel synthesis efficiently optimized M5 potency to arrive at the most potent M5 PAMs prepared to date and provided tool compound 8n (ML380) demonstrating modest CNS penetration (human M5 EC50 = 190 nM, rat M5 EC50 = 610 nM, brain to plasma ratio (Kp) of 0.36).

The content you want is available to Zendy users.

Already have an account? Click here to sign in.

Having issues? You can contact us here

Accelerating Research