Further optimization of the M5 NAM MLPCN probe ML375: tactics and challenges
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Further optimization of the M5 NAM MLPCN probe ML375 : tactics and challenges. / Kurata, Haruto; Gentry, Patrick R; Kokubo, Masaya; Cho, Hyekyung P; Bridges, Thomas M; Niswender, Colleen M; Byers, Frank W; Wood, Michael R; Daniels, J Scott; Conn, P Jeffrey; Lindsley, Craig W.
In: Bioorganic & Medicinal Chemistry Letters, Vol. 25, No. 3, 01.02.2015, p. 690-4.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Further optimization of the M5 NAM MLPCN probe ML375
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
N1 - Copyright © 2014 Elsevier Ltd. All rights reserved.
PY - 2015/2/1
Y1 - 2015/2/1
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
VL - 25
SP - 690
EP - 694
JO - Bioorganic & Medicinal Chemistry Letters
JF - Bioorganic & Medicinal Chemistry Letters
SN - 0960-894X
IS - 3
ER -
ID: 213599333