Discovery of ML326: The first sub-micromolar, selective M5 PAM

Patrick R Gentry; Thomas M Bridges; Atin Lamsal; Paige N Vinson; Emery Smith; Peter Chase; Peter S Hodder; Julie L Engers; Colleen M Niswender; J Scott Daniels; P Jeffrey Conn; Michael R Wood; Craig W Lindsley

doi:10.1016/j.bmcl.2013.03.032

Discovery of ML326: The first sub-micromolar, selective M5 PAM

Patrick R Gentry, Thomas M Bridges, Atin Lamsal, Paige N Vinson, Emery Smith, Peter Chase, Peter S Hodder, Julie L Engers, Colleen M Niswender, J Scott Daniels, P Jeffrey Conn, Michael R Wood, Craig W Lindsley

15 Citations (Scopus)

Abstract

This Letter describes the further chemical optimization of the M5 PAM MLPCN probes ML129 and ML172. A multi-dimensional iterative parallel synthesis effort quickly explored isatin replacements and a number of southern heterobiaryl variations with no improvement over ML129 and ML172. An HTS campaign identified several weak M5 PAMs (M5 EC50 >10μM) with a structurally related isatin core that possessed a southern phenethyl ether linkage. While SAR within the HTS series was very shallow and unable to be optimized, grafting the phenethyl ether linkage onto the ML129/ML172 cores led to the first sub-micromolar M5 PAM, ML326 (VU0467903), (human and rat M5 EC50s of 409nM and 500nM, respectively) with excellent mAChR selectivity (M1-M4 EC50s >30μM) and a robust 20-fold leftward shift of the ACh CRC.

Original language	English
Journal	Bioorganic & Medicinal Chemistry Letters
Volume	23
Issue number	10
Pages (from-to)	2996-3000
Number of pages	5
ISSN	0960-894X
DOIs	https://doi.org/10.1016/j.bmcl.2013.03.032
Publication status	Published - 15 May 2013
Externally published	Yes

Keywords

Animals
Dose-Response Relationship, Drug
Drug Discovery
Humans
Indoles/chemical synthesis
Molecular Structure
Rats
Receptors, Muscarinic/metabolism
Structure-Activity Relationship

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10.1016/j.bmcl.2013.03.032

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title = "Discovery of ML326: The first sub-micromolar, selective M5 PAM",

abstract = "This Letter describes the further chemical optimization of the M5 PAM MLPCN probes ML129 and ML172. A multi-dimensional iterative parallel synthesis effort quickly explored isatin replacements and a number of southern heterobiaryl variations with no improvement over ML129 and ML172. An HTS campaign identified several weak M5 PAMs (M5 EC50 >10μM) with a structurally related isatin core that possessed a southern phenethyl ether linkage. While SAR within the HTS series was very shallow and unable to be optimized, grafting the phenethyl ether linkage onto the ML129/ML172 cores led to the first sub-micromolar M5 PAM, ML326 (VU0467903), (human and rat M5 EC50s of 409nM and 500nM, respectively) with excellent mAChR selectivity (M1-M4 EC50s >30μM) and a robust 20-fold leftward shift of the ACh CRC.",

keywords = "Animals, Dose-Response Relationship, Drug, Drug Discovery, Humans, Indoles/chemical synthesis, Molecular Structure, Rats, Receptors, Muscarinic/metabolism, Structure-Activity Relationship",

author = "Gentry, {Patrick R} and Bridges, {Thomas M} and Atin Lamsal and Vinson, {Paige N} and Emery Smith and Peter Chase and Hodder, {Peter S} and Engers, {Julie L} and Niswender, {Colleen M} and Daniels, {J Scott} and Conn, {P Jeffrey} and Wood, {Michael R} and Lindsley, {Craig W}",

year = "2013",

month = may,

day = "15",

doi = "10.1016/j.bmcl.2013.03.032",

language = "English",

volume = "23",

pages = "2996--3000",

journal = "Bioorganic & Medicinal Chemistry Letters",

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T1 - Discovery of ML326

T2 - The first sub-micromolar, selective M5 PAM

AU - Gentry, Patrick R

AU - Bridges, Thomas M

AU - Lamsal, Atin

AU - Vinson, Paige N

AU - Smith, Emery

AU - Chase, Peter

AU - Hodder, Peter S

AU - Engers, Julie L

AU - Niswender, Colleen M

AU - Daniels, J Scott

AU - Conn, P Jeffrey

AU - Wood, Michael R

AU - Lindsley, Craig W

PY - 2013/5/15

Y1 - 2013/5/15

N2 - This Letter describes the further chemical optimization of the M5 PAM MLPCN probes ML129 and ML172. A multi-dimensional iterative parallel synthesis effort quickly explored isatin replacements and a number of southern heterobiaryl variations with no improvement over ML129 and ML172. An HTS campaign identified several weak M5 PAMs (M5 EC50 >10μM) with a structurally related isatin core that possessed a southern phenethyl ether linkage. While SAR within the HTS series was very shallow and unable to be optimized, grafting the phenethyl ether linkage onto the ML129/ML172 cores led to the first sub-micromolar M5 PAM, ML326 (VU0467903), (human and rat M5 EC50s of 409nM and 500nM, respectively) with excellent mAChR selectivity (M1-M4 EC50s >30μM) and a robust 20-fold leftward shift of the ACh CRC.

AB - This Letter describes the further chemical optimization of the M5 PAM MLPCN probes ML129 and ML172. A multi-dimensional iterative parallel synthesis effort quickly explored isatin replacements and a number of southern heterobiaryl variations with no improvement over ML129 and ML172. An HTS campaign identified several weak M5 PAMs (M5 EC50 >10μM) with a structurally related isatin core that possessed a southern phenethyl ether linkage. While SAR within the HTS series was very shallow and unable to be optimized, grafting the phenethyl ether linkage onto the ML129/ML172 cores led to the first sub-micromolar M5 PAM, ML326 (VU0467903), (human and rat M5 EC50s of 409nM and 500nM, respectively) with excellent mAChR selectivity (M1-M4 EC50s >30μM) and a robust 20-fold leftward shift of the ACh CRC.

KW - Animals

KW - Dose-Response Relationship, Drug

KW - Drug Discovery

KW - Humans

KW - Indoles/chemical synthesis

KW - Molecular Structure

KW - Rats

KW - Receptors, Muscarinic/metabolism

KW - Structure-Activity Relationship

U2 - 10.1016/j.bmcl.2013.03.032

DO - 10.1016/j.bmcl.2013.03.032

M3 - Journal article

C2 - 23562060

SN - 0960-894X

VL - 23

SP - 2996

EP - 3000

JO - Bioorganic & Medicinal Chemistry Letters

JF - Bioorganic & Medicinal Chemistry Letters

IS - 10

ER -

Discovery of ML326: The first sub-micromolar, selective M5 PAM

Abstract

Keywords

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