76315-01-0Relevant articles and documents
Scale-Up Synthesis of IID572: A New β-Lactamase Inhibitor
Casarez, Anthony,Furegati, Markus,Koch, Guido,Nocito, Sandro,Reck, Folkert,Schuetz, Heiner,Simmons, Robert
, p. 1244 - 1253 (2020)
The new potentially best-in-class β-lactamase inhibitor IID572 was discovered by a late-stage functionalization approach. An alternative synthesis was developed to satisfy the short-term material need for toxicological studies in animals. The new synthetic strategy was built on two key features, an intramolecular azomethine ylide [3 + 2] cycloaddition that allowed the efficient formation of molecular complexity from readily available starting materials and an enzymatic resolution that resulted in high optical purity of a key intermediate.
Cyclic Poly(α-peptoid)s by Lithium bis(trimethylsilyl)amide (LiHMDS)-Mediated Ring-Expansion Polymerization: Simple Access to Bioactive Backbones
Salas-Ambrosio, Pedro,Tronnet, Antoine,Since, Marc,Bourgeade-Delmas, Sandra,Stigliani, Jean-Luc,Vax, Amelie,Lecommandoux, Sébastien,Dupuy, Bruno,Verhaeghe, Pierre,Bonduelle, Colin
supporting information, p. 3697 - 3702 (2021/04/07)
Cyclic polymers display unique physicochemical and biological properties. However, their development is often limited by their challenging preparation. In this work, we present a simple route to cyclic poly(α-peptoids) from N-alkylated-N-carboxyanhydrides (NNCA) using LiHMDS promoted ring-expansion polymerization (REP) in DMF. This new method allows the unprecedented use of lysine-like monomers in REP to design bioactive macrocycles bearing pharmaceutical potential against Clostridioides difficile, a bacterium responsible for nosocomial infections.
NOVEL SELECTIVE KAPPA OPIOID RECEPTOR ANTAGONISTS AND METHODS RELATED THERETO FOR TREATMENT OF ADDICTION AND NEUROPATHIC PAIN
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Paragraph 00076, (2020/05/28)
Disclosed is a composition and method for a therapeutic treatment that is able to combat certain conditions such as addiction, alcohol dependence, opioid abuse treatment, neurological disorders, neuropathic pain, and combinations thereof. The compounds act by acting as selective antagonist to the kappa (K) opioid receptor, which, when present leads to the inhibition of conditions, providing increased performance over known treatments. The disclosed compounds also shows the ability to cross the blood-brain-barrier in a highly efficient manner. The disclosed compounds are shown to be effective in the nanomolar range.
Discovery of SHR0687, a Highly Potent and Peripheral Nervous System-Restricted KOR Agonist
Li, Xin,Wan, Hong,Dong, Ping,Wang, Bin,Zhang, Lei,Hu, Qiyue,Zhang, Ting,Feng, Jun,He, Feng,Bai, Chang,Zhang, Lianshan,Tao, Weikang
supporting information, p. 2151 - 2155 (2020/12/17)
Analgesics with no abuse liability are highly demanded in the market. KOR agonists have been proved to be strong analgesics without MOR agonist-related side effects, such as respiratory depression, tolerance, and dependence liability; however, activation
Design, Synthesis, and Pharmacokinetic Evaluation of Phosphate and Amino Acid Ester Prodrugs for Improving the Oral Bioavailability of the HIV-1 Protease Inhibitor Atazanavir
Subbaiah, Murugaiah A.M.,Mandlekar, Sandhya,Desikan, Sridhar,Ramar, Thangeswaran,Subramani, Lakshumanan,Annadurai, Mathiazhagan,Desai, Salil D.,Sinha, Sarmistha,Jenkins, Susan M.,Krystal, Mark R.,Subramanian, Murali,Sridhar, Srikanth,Padmanabhan, Shweta,Bhutani, Priyadeep,Arla, Rambabu,Singh, Shashyendra,Sinha, Jaydeep,Thakur, Megha,Kadow, John F.,Meanwell, Nicholas A.
, p. 3553 - 3574 (2019/04/17)
Phosphate and amino acid prodrugs of the HIV-1 protease inhibitor (PI) atazanavir (1) were prepared and evaluated to address solubility and absorption limitations. While the phosphate prodrug failed to release 1 in rats, the introduction of a methylene spacer facilitated prodrug activation, but parent exposure was lower than that following direct administration of 1. Val amino acid and Val-Val dipeptides imparted low plasma exposure of the parent, although the exposure of the prodrugs was high, reflecting good absorption. Screening of additional amino acids resulted in the identification of an l-Phe ester that offered an improved exposure of 1 and reduced levels of the circulating prodrug. Further molecular editing focusing on the linker design culminated in the discovery of the self-immolative l-Phe-Sar dipeptide derivative 74 that gave four-fold improved AUC and eight-fold higher Ctrough values of 1 compared with oral administration of the drug itself, demonstrating a successful prodrug approach to the oral delivery of 1.
BETA-LACTAMASE INHIBITORS
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Paragraph 00203, (2018/04/17)
This invention pertains generally to compounds of Formula (A), as further described herein, which act as beta-lactamase inhibitors, and salts, crystalline forms and formulations thereof. In certain aspects, the invention pertains to methods of using such
Structure-activity relationships of imidazole-derived 2-[ N-carbamoylmethyl-alkylamino]acetic acids, dual binders of human insulin-degrading enzyme
Charton, Julie,Gauriot, Marion,Totobenazara, Jane,Hennuyer, Nathalie,Dumont, Julie,Bosc, Damien,Marechal, Xavier,Elbakali, Jamal,Herledan, Adrien,Wen, Xiaoan,Ronco, Cyril,Gras-Masse, Helene,Heninot, Antoine,Pottiez, Virginie,Landry, Valerie,Staels, Bart,Liang, Wenguang G.,Leroux, Florence,Tang, Wei-Jen,Deprez, Benoit,Deprez-Poulain, Rebecca
, p. 547 - 567 (2015/03/18)
Insulin degrading enzyme (IDE) is a zinc metalloprotease that degrades small amyloid peptides such as amyloid-a and insulin. So far the dearth of IDE-specific pharmacological inhibitors impacts the understanding of its role in the physiopathology of Alzheimer's disease, amyloid-a clearance, and its validation as a potential therapeutic target. Hit 1 was previously discovered by high-throughput screening. Here we describe the structure-activity study, that required the synthesis of 48 analogues. We found that while the carboxylic acid, the imidazole and the tertiary amine were critical for activity, the methyl ester was successfully optimized to an amide or a 1,2,4-oxadiazole. Along with improving their activity, compounds were optimized for solubility, lipophilicity and stability in plasma and microsomes. The docking or co-crystallization of some compounds at the exosite or the catalytic site of IDE provided the structural basis for IDE inhibition. The pharmacokinetic properties of best compounds 44 and 46 were measured in vivo. As a result, 44 (BDM43079) and its methyl ester precursor 48 (BDM43124) are useful chemical probes for the exploration of IDE's role.
ARYLPROPIONAMIDE, ARYLACRYLAMIDE, ARYLPROPYNAMIDE, OR ARYLMETHYLUREA ANALOGS AS FACTOR XIA INHIBITORS
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Page/Page column 63, (2010/02/17)
The present invention provides compounds of Formula (I) or (II): or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate form thereof, wherein the variables A, L1, R3, R4, R8a, R11 and M are as defined herein. The compounds of Formula (I) or (II) are selective inhibitors of serine protease enzymes of the coagulation cascade and/or contact activation system; for example thrombin, factor Xa, factor XIa, factor IXa, factor VIIa and/or plasma kallikrein. In particular, it relates to compounds that are selective factor XIa inhibitors or dual inhibitors of fXIa and plasma kallikrein. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and/or inflammatory disorders using the same.
Weinreb amide based synthetic equivalents for convenient access to 4-aryl-1,2,3,4-tetrahydroisoquinolines
Kommidi, Harikrishna,Balasubramaniam, Sivaraman,Aidhen, Indrapal Singh
scheme or table, p. 3723 - 3729 (2010/07/05)
New synthetic equivalents, N-methoxy-N-methyl-N′-phenylsulfonyl glycinamide and N-methoxy-N-methyl-N′-benzyl-N′-tert-butyloxy carbonyl glycinamide based on WA functionality were developed for the convenient synthesis of 4-aryl-1,2,3,4-tetrahydroisoquinoline framework. Two simple reactions, N-benzylation and addition of arylmagnesium halide on the WA functionality of the former afforded the key intermediate for convenient synthesis of N-phenylsulfonyl protected 4-aryl-1,2,3,4-tetrahydroisoquinoline, through reduction and acid promoted cyclization. With the latter, the addition of arylmagnesium halide on the WA functionality followed by the same protocol afforded the direct synthesis of 4-aryl-1,2,3,4-tetrahydroisoquinolines in good yields. The acid promoted cyclization step enabled concomitant removal of N-Boc protection.
ARYLPROPIONAMIDE, ARYLACRYLAMIDE, ARYLPROPYNAMIDE, OR ARYLMETHYLUREA ANALOGS AS FACTOR XIA INHIBITORS
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Page/Page column 127, (2008/12/06)
The present invention provides compounds of Formula (I) or (II): or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate form thereof, wherein the variables A, L1, R3, R4, R8a, R11 and M are as defined herein. The compounds of Formula (I) or (II) are selective inhibitors of serine protease enzymes of the coagulation cascade and/or contact activation system; for example thrombin, factor Xa, factor XIa, factor IXa, factor VIIa and/or plasma kallikrein. In particular, it relates to compounds that are selective factor XIa inhibitors or dual inhibitors of fXIa and plasma kallikrein. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and/or inflammatory disorders using the same.
