51671-71-7Relevant academic research and scientific papers
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.
, p. 690 - 694 (2015/01/30)
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.
A Novel Series of Selective, Non-Peptide Inhibitors of Angiotensin II Binding to the AT2 Site
VanAtten, Mary K.,Ensinger, Carol L.,Chiu, Andrew T.,McCall, Dale E.,Nguyen, Tam T.,et al.
, p. 3985 - 3992 (2007/10/02)
The availability of peptide and non-peptide Ang II receptor antagonists has permitted the study of Ang II receptor heterogeneity.It is now widely recognized that there are at least two distinct Ang II receptor subtypes.AT1 receptors are selective in their recognition of agents such as losartan, DuP 532,L-158,809,SKF108566, and similar non-peptides.To date, all of the well-known actions of Ang II in mammals are blocked by the AT1 selective antagonists such as losartan and are thus designated as being mediated by the AT1 receptor.Although there have been reports of functional activity mediated through AT2 sites, the pharmacological role for the AT2 receptor has not yet been elucidated.Herein, we report the chemistry and SAR on a novel series of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids which have selective affinity for AT2 receptors.The most potent of which (19) has an IC50 of 30 nM for the AT2 receptor in the rat adrenal radioligand binding assay.
