444583-19-1Relevant articles and documents
Discovery of Tetrahydroisoquinoline-Containing CXCR4 Antagonists with Improved in Vitro ADMET Properties
Miller, Eric J.,Jecs, Edgars,Truax, Valarie M.,Katzman, Brooke M.,Tahirovic, Yesim A.,Wilson, Robert J.,Kuo, Katie M.,Kim, Michelle B.,Nguyen, Huy H.,Saindane, Manohar T.,Zhao, Huanyu,Wang, Tao,Sum, Chi S.,Cvijic, Mary E.,Schroeder, Gretchen M.,Wilson, Lawrence J.,Liotta, Dennis C.
, p. 946 - 979 (2018/02/17)
CXCR4 is a seven-transmembrane receptor expressed by hematopoietic stem cells and progeny, as well as by ≥48 different cancers types. CXCL12, the only chemokine ligand of CXCR4, is secreted within the tumor microenvironment, providing sanctuary for CXCR4+ tumor cells from immune surveillance and chemotherapeutic elimination by (1) stimulating prosurvival signaling and (2) recruiting CXCR4+ immunosuppressive leukocytes. Additionally, distant CXCL12-rich niches attract and support CXCR4+ metastatic growths. Accordingly, CXCR4 antagonists can potentially obstruct CXCR4-mediated prosurvival signaling, recondition the CXCR4+ leukocyte infiltrate from immunosuppressive to immunoreactive, and inhibit CXCR4+ cancer cell metastasis. Current small molecule CXCR4 antagonists suffer from poor oral bioavailability and off-target liabilities. Herein, we report a series of novel tetrahydroisoquinoline-containing CXCR4 antagonists designed to improve intestinal absorption and off-target profiles. Structure-activity relationships regarding CXCR4 potency, intestinal permeability, metabolic stability, and cytochrome P450 inhibition are presented.
Synthesis and SAR of 1,2,3,4-Tetrahydroisoquinoline-Based CXCR4 Antagonists
Wilson, Robert J.,Jecs, Edgars,Miller, Eric J.,Nguyen, Huy H.,Tahirovic, Yesim A.,Truax, Valarie M.,Kim, Michelle B.,Kuo, Katie M.,Wang, Tao,Sum, Chi Shing,Cvijic, Mary E.,Paiva, Anthony A.,Schroeder, Gretchen M.,Wilson, Lawrence J.,Liotta, Dennis C.
, p. 17 - 22 (2018/05/04)
CXCR4 is the most common chemokine receptor expressed on the surface of many cancer cell types. In comparison to normal cells, cancer cells overexpress CXCR4, which correlates with cancer cell metastasis, angiogenesis, and tumor growth. CXCR4 antagonists can potentially diminish the viability of cancer cells by interfering with CXCL12-mediated pro-survival signaling and by inhibiting chemotaxis. Herein, we describe a series of CXCR4 antagonists that are derived from (S)-5,6,7,8-tetrahydroquinolin-8-amine that has prevailed in the literature. This series removes the rigidity and chirality of the tetrahydroquinoline providing 2-(aminomethyl)pyridine analogs, which are more readily accessible and exhibit improved liver microsomal stability. The medicinal chemistry strategy and biological properties are described.
TETRAHYDROISOQUINOLINE DERIVED PRMT5-INHIBITORS
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, (2016/03/19)
A compound of formula I wherein: n is 1 or 2: p is 0 or 1; R1 is optionally one or more halo or methyl groups; R2a and R2b are independently selected from the group consisting of: (i) F; (ii) H; (iii) Me; and (iv) CH2OH; R2c and R2d are independently selected from the group consisting of: (i) F; (ii) H; (iii) Me; and (iv) CH2OH; R3a and R3b are independently selected from H and Me; R4 is either H or Me; R5 is either H or Me; R6a and R6b are independently selected from H and Me; A is either (i) optionally substituted phenyl; (ii) optionally substituted naphthyl; or (iii) optionally substituted C5-12 heteroaryl.
Discovery of tetrahydroisoquinoline-based CXCR4 antagonists
Truax, Valarie M.,Zhao, Huanyu,Katzman, Brooke M.,Prosser, Anthony R.,Alcaraz, Ana A.,Saindane, Manohar T.,Howard, Randy B.,Culver, Deborah,Arrendale, Richard F.,Gruddanti, Prahbakar R.,Evers, Taylor J.,Natchus, Michael G.,Snyder, James P.,Liotta, Dennis C.,Wilson, Lawrence J.
supporting information, p. 1025 - 1030 (2013/12/04)
A de novo hit-to-lead effort involving the redesign of benzimidazole- containing antagonists of the CXCR4 receptor resulted in the discovery of a novel series of 1,2,3,4-tetrahydroisoquinoline (TIQ) analogues. In general, this series of compounds show good potencies (3-650 nM) in assays involving CXCR4 function, including both inhibition of attachment of X4 HIV-1IIIB virus in MAGI-CCR5/CXCR4 cells and inhibition of calcium release in Chem-1 cells. Series profiling permitted the identification of TIQ-(R)-stereoisomer 15 as a potent and selective CXCR4 antagonist lead candidate with a promising in vitro profile. The drug-like properties of 15 were determined in ADME in vitro studies, revealing low metabolic liability potential. Further in vivo evaluations included pharmacokinetic experiments in rats and mice, where 15 was shown to have oral bioavailability (F = 63%) and resulted in the mobilization of white blood cells (WBCs) in a dose-dependent manner.
Impact of distinct chemical structures for the development of a methamphetamine vaccine
Moreno, Amira Y.,Mayorov, Alexander V.,Janda, Kim D.
supporting information; experimental part, p. 6587 - 6595 (2011/06/27)
(+)-Methamphetamine (METH) use and addiction has grown at alarming rates over the past two decades, while no approved pharmacotherapy exists for its treatment. Immunopharmacotherapy has the potential to offer relief through producing highly specific antibodies that prevent drug penetration across the blood-brain barrier thus decreasing reinforcement of the behavior. Current immunotherapy efforts against methamphetamine have focused on a single hapten structure, namely linker attachment at the aromatic ring of the METH molecule. Hapten design is largely responsible for immune recognition, as it affects presentation of the target antigen and thus the quality of the response. In the current paper we report the systematic generation of a series of haptens designed to target the most stable conformations of methamphetamine as determined by molecular modeling. On the basis of our previous studies with nicotine, we show that introduction of strategic molecular constraint is able to maximize immune recognition of the target structure as evidenced by higher antibody affinity. Vaccination of GIX+ mice with six unique METH immunoconjugates resulted in high antibody titers for three particularly promising formulations (45-108 μg/mL, after the second immunization) and high affinity (82, 130, and 169 nM for MH2, MH6, and MH7 hapten-based vaccines, respectively). These findings represent a unique approach to the design of new vaccines against methamphetamine abuse.
Substituted Tetrahydroisoquinolines as Beta-secretase Inhibitors
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Page/Page column 16, (2008/12/06)
There is provided a series of tetrahydroisoquinoline diaminopropane compounds of Formula (I) or a stereoisomer; or a pharmaceutically acceptable salt thereof, wherein R, R8 and R9 are as defined herein, their pharmaceutical compositi
C-terminal constrained phenylalanine as a pharmacophoric unit in peptide-based proteasome inhibitors
Baldisserotto, Anna,Marastoni, Mauro,Lazzari, Ilaria,Trapella, Claudio,Gavioli, Riccardo,Tomatis, Roberto
, p. 1403 - 1411 (2008/12/20)
Here we report the synthesis and biological properties of peptide-based molecules bearing constrained analogues of phenylalanine at the C-terminal. Compounds were tested as proteasome subunits' inhibitors. Dehydro-peptides showed good inhibition, in particular against trypsin-like (T-L) proteasome activity while some C-terminal Tic-derivatives inhibit only caspase-like activity in enzymatic β1 subunits with a certain degree of efficacy. The best analogues of the series demonstrated good resistance to proteolysis and a capacity to permeate the cell membrane.
AMINOTROPANE DERIVATIVES, PREPARATION THEREOF AND THERAPEUTIC USE THEREOF
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Page/Page column 17, (2008/06/13)
The present invention relates to compounds of formula (I) as defined herein that are melanocortin receptor agonists, to the preparation thereof and to the therapeutic use thereof in the treatment and in the prevention of obesity, diabetes and sexual dysfunctions that can affect both sexes, in the treatment of cardiovascular diseases, and also in anti-inflammatory uses or in the treatment of alcohol dependency.
Synthesis and structure-activity relationships of novel dipeptides and reduced dipeptides as ligands for melanocortin subtype-4 receptor
Shi, Qing,Ornstein, Paul L.,Briner, Karin,Richardson, Timothy I.,Arnold, Macklin B.,Backer, Ryan T.,Buckmaster, Jennifer L.,Canada, Emily J.,Doecke, Christopher W.,Hertel, Larry W.,Honigschmidt, Nick,Hsiung, Hansen M.,Husain, Saba,Kuklish, Steve L.,Martinelli, Michael J.,Mullaney, Jeffrey T.,O'Brien, Thomas P.,Reinhard, Matt R.,Rothhaar, Roger,Shah, Jikesh,Wu, Zhipei,Xie, Chaoyu,Zgombick, John M.,Fisher, Matthew J.
, p. 2341 - 2346 (2007/10/03)
A series of benzylic piperazines (e.g., 4 and 5) attached to an 'address element', the dipeptide H-d-Tic-d-p-Cl-Phe-OH, 3 has been identified as ligands for the melanocortin subtype-4 receptor (MC4R). We describe herein the structure-activity relationship (SAR) studies on the N-terminal residue of the 'address element'. Several novel dipeptides and reduced dipeptides with high MC4R binding affinities and selectivity emerged from this SAR study.
Synthetic investigations of (1,3′)-bistetrahydroisoquinolines: Towards pentacyclic analogues of piperazine core alkaloids
Aubry, Sylvain,Pellet-Rostaing, Stéphane,Fenet, Bernard,Lemaire, Marc
, p. 1319 - 1323 (2007/10/03)
Synthetic investigations of (1,3′)-bistetrahydroisoquinolines are reported as the key intermediates for the synthesis of ecteinascidin and phthalascidin pentacyclic structure analogues through successive Pictet-Spengler cyclization and intramolecular peptide coupling. The direct Pictet-Spengler reaction between a derivative of l-DOPA and N-protected-α-aminoaldehyde was first extended to the synthesis of cis-(1,3′)- bistetrahydroisoquinoline. After introduction of the required amino acid moiety, an efficient six-membered ring intramolecular peptide coupling gave rise to piperazine derivative structures. Complete structural assignments were corroborated by NMR and X-ray spectroscopic methods. Nevertheless, the optical integrity of the N-protected-α-aminoaldehyde seems to be sensitive to the reaction conditions. Pentacylic structures, having an anti C3-C11 backbone stereochemistry, were obtained from cyclization para- and ortho- to the 3-OH group of the l-DOPA derivative.
