Further optimization of the M5 NAM MLPCN probe ML375: tactics and challenges

Haruto Kurata; Patrick R Gentry; Masaya Kokubo; Hyekyung P Cho; Thomas M Bridges; Colleen M Niswender; Frank W Byers; Michael R Wood; J Scott Daniels; P Jeffrey Conn; Craig W Lindsley

doi:10.1016/j.bmcl.2014.11.082

Further optimization of the M5 NAM MLPCN probe ML375: tactics and challenges

Haruto Kurata, Patrick R Gentry, Masaya Kokubo, Hyekyung P Cho, Thomas M Bridges, Colleen M Niswender, Frank W Byers, Michael R Wood, J Scott Daniels, P Jeffrey Conn, Craig W Lindsley

12 Citationer (Scopus)

Abstract

This Letter describes the continued optimization of the MLPCN probe ML375, a highly selective M5 negative allosteric modulator (NAM), through a combination of matrix libraries and iterative parallel synthesis. True to certain allosteric ligands, SAR was shallow, and the matrix library approach highlighted the challenges with M5 NAM SAR within in this chemotype. Once again, enantiospecific activity was noted, and potency at rat and human M5 were improved over ML375, along with slight enhancement in physiochemical properties, certain in vitro DMPK parameters and CNS distribution. Attempts to further enhance pharmacokinetics with deuterium incorporation afforded mixed results, but pretreatment with a pan-P450 inhibitor (1-aminobenzotriazole; ABT) provided increased plasma exposure.

Originalsprog	Engelsk
Tidsskrift	Bioorganic & Medicinal Chemistry Letters
Vol/bind	25
Udgave nummer	3
Sider (fra-til)	690-4
Antal sider	5
ISSN	0960-894X
DOI	https://doi.org/10.1016/j.bmcl.2014.11.082
Status	Udgivet - 1 feb. 2015
Udgivet eksternt	Ja

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10.1016/j.bmcl.2014.11.082

Citationsformater

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title = "Further optimization of the M5 NAM MLPCN probe ML375: tactics and challenges",

abstract = "This Letter describes the continued optimization of the MLPCN probe ML375, a highly selective M5 negative allosteric modulator (NAM), through a combination of matrix libraries and iterative parallel synthesis. True to certain allosteric ligands, SAR was shallow, and the matrix library approach highlighted the challenges with M5 NAM SAR within in this chemotype. Once again, enantiospecific activity was noted, and potency at rat and human M5 were improved over ML375, along with slight enhancement in physiochemical properties, certain in vitro DMPK parameters and CNS distribution. Attempts to further enhance pharmacokinetics with deuterium incorporation afforded mixed results, but pretreatment with a pan-P450 inhibitor (1-aminobenzotriazole; ABT) provided increased plasma exposure. ",

keywords = "Allosteric Regulation, Animals, Brain/metabolism, Half-Life, Humans, Imidazoles/chemistry, Indoles/chemistry, Microsomes, Liver/metabolism, Protein Binding, Rats, Receptor, Muscarinic M5/chemistry, Structure-Activity Relationship",

author = "Haruto Kurata and Gentry, {Patrick R} and Masaya Kokubo and Cho, {Hyekyung P} and Bridges, {Thomas M} and Niswender, {Colleen M} and Byers, {Frank W} and Wood, {Michael R} and Daniels, {J Scott} and Conn, {P Jeffrey} and Lindsley, {Craig W}",

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language = "English",

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T2 - tactics and challenges

AU - Kurata, Haruto

AU - Gentry, Patrick R

AU - Kokubo, Masaya

AU - Cho, Hyekyung P

AU - Bridges, Thomas M

AU - Niswender, Colleen M

AU - Byers, Frank W

AU - Wood, Michael R

AU - Daniels, J Scott

AU - Conn, P Jeffrey

AU - Lindsley, Craig W

PY - 2015/2/1

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N2 - This Letter describes the continued optimization of the MLPCN probe ML375, a highly selective M5 negative allosteric modulator (NAM), through a combination of matrix libraries and iterative parallel synthesis. True to certain allosteric ligands, SAR was shallow, and the matrix library approach highlighted the challenges with M5 NAM SAR within in this chemotype. Once again, enantiospecific activity was noted, and potency at rat and human M5 were improved over ML375, along with slight enhancement in physiochemical properties, certain in vitro DMPK parameters and CNS distribution. Attempts to further enhance pharmacokinetics with deuterium incorporation afforded mixed results, but pretreatment with a pan-P450 inhibitor (1-aminobenzotriazole; ABT) provided increased plasma exposure.

AB - This Letter describes the continued optimization of the MLPCN probe ML375, a highly selective M5 negative allosteric modulator (NAM), through a combination of matrix libraries and iterative parallel synthesis. True to certain allosteric ligands, SAR was shallow, and the matrix library approach highlighted the challenges with M5 NAM SAR within in this chemotype. Once again, enantiospecific activity was noted, and potency at rat and human M5 were improved over ML375, along with slight enhancement in physiochemical properties, certain in vitro DMPK parameters and CNS distribution. Attempts to further enhance pharmacokinetics with deuterium incorporation afforded mixed results, but pretreatment with a pan-P450 inhibitor (1-aminobenzotriazole; ABT) provided increased plasma exposure.

KW - Allosteric Regulation

KW - Animals

KW - Brain/metabolism

KW - Half-Life

KW - Humans

KW - Imidazoles/chemistry

KW - Indoles/chemistry

KW - Microsomes, Liver/metabolism

KW - Protein Binding

KW - Rats

KW - Receptor, Muscarinic M5/chemistry

KW - Structure-Activity Relationship

U2 - 10.1016/j.bmcl.2014.11.082

DO - 10.1016/j.bmcl.2014.11.082

M3 - Journal article

C2 - 25542588

SN - 0960-894X

VL - 25

SP - 690

EP - 694

JO - Bioorganic & Medicinal Chemistry Letters

JF - Bioorganic & Medicinal Chemistry Letters

IS - 3

ER -

Further optimization of the M5 NAM MLPCN probe ML375: tactics and challenges

Abstract

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