- Design, synthesis and in vitro evaluation of novel SARS-CoV-2 3CLpro covalent inhibitors
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Severe diseases such as the ongoing COVID-19 pandemic, as well as the previous SARS and MERS outbreaks, are the result of coronavirus infections and have demonstrated the urgent need for antiviral drugs to combat these deadly viruses. Due to its essential role in viral replication and function, 3CLpro (main coronaviruses cysteine-protease) has been identified as a promising target for the development of antiviral drugs. Previously reported SARS-CoV 3CLpro non-covalent inhibitors were used as a starting point for the development of covalent inhibitors of SARS-CoV-2 3CLpro. We report herein our efforts in the design and synthesis of submicromolar covalent inhibitors when the enzymatic activity of the viral protease was used as a screening platform.
- Stille, Julia K.,Tjutrins, Jevgenijs,Wang, Guanyu,Venegas, Felipe A.,Hennecker, Christopher,Rueda, Andrés M.,Sharon, Itai,Blaine, Nicole,Miron, Caitlin E.,Pinus, Sharon,Labarre, Anne,Plescia, Jessica,Burai Patrascu, Mihai,Zhang, Xiaocong,Wahba, Alexander S.,Vlaho, Danielle,Huot, Mitchell J.,Schmeing, T. Martin,Mittermaier, Anthony K.,Moitessier, Nicolas
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- NOVEL TETRAHYDROISOQUINOLINES AND TERAHYDRONAPHTHYRIDINES FOR THE TREATMENT AND PROPHYLAXIS OF HEPATITIS B VIRUS INFECTION
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The present invention provides novel compounds having the general formula (I): wherein R1, R 2, R 3, U, V, W, X and Y are as described herein, compositions including the compounds and methods of using the compounds.
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Page/Page column 29; 30
(2018/05/24)
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- Enantioselective formal aza-Diels-Alder reactions of enones with cyclic imines catalyzed by primary aminothioureas
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A highly enantio- and diastereoselective synthesis of indolo- and benzoquinolizidine compounds has been developed through the formal aza-Diels-Alder reaction of enones with cyclic imines. This transformation is catalyzed by a new bifunctional primary aminothiourea that achieves simultaneous activation of both the enone and imine reaction components.
- Lalonde, Mathieu P.,McGowan, Meredeth A.,Rajapaksa, Naomi S.,Jacobsen, Eric N.
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supporting information
p. 1891 - 1894
(2013/04/10)
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- Structure-activity correlations for β-phenethylamines at human trace amine receptor 1
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A cell line in which RD-HGA16 cells were stably transfected with the hTAAR 1 receptor was created and utilized to carry out a systematic evaluation of a series of β-phenethylamines. Fair agreement was observed with data obtained for aryl and ethylene chain substituted analogs in an AV12-664 cell line in which hemagglutinin-tagged hTAAR 1 was stably co-expressed with rat Gαs. Analogs with multiple substituents as well as analogs with bulky groups were found to be partial agonists. Analogs in which the primary amino group was converted to a secondary or a tertiary amino group by N-methylation were also partial agonists. Comparative Molecular Field Analysis (CoMFA) using the potency data yielded a regression coefficient r2 of 0.824. The steric field contribution to the model was 61% with the balance (39%) contributed by the electrostatic field. The collective results suggest that increasing steric bulk both at the amino nitrogen, particularly by N-dimethylation, and at the 4-position of the aromatic ring leads to low efficacy ligands.
- Lewin, Anita H.,Navarro, Hernan A.,Wayne Mascarella
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p. 7415 - 7423
(2008/12/22)
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- Synthesis and pharmacology of benzoxazines as highly selective antagonists at M4 muscarinic receptors
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Previously, we reported on PD 102807 (41) as being the most selective synthetic M4 muscarinic antagonist identified to date. Synthesized analogues of 41 showed no improvement in affinity and selectivity at that time. However, several newly synthesized compounds exhibit a 7-fold higher affinity at M4 receptors and demonstrate a selectivity of at least 100-fold over all other muscarinic receptor subtypes. For example, compound 28 showed an affinity of pKi = 9.00 at M4 receptors and a selectivity of M1/M4 13 183-fold, M2/M4 = 339-fold, M3/M4 = 151-fold, and M5/M4 = 11 220-fold. This high selectivity along with high affinity has not been reported for any synthetic muscarinic antagonist, nor for natural occurring M4 antagonists such as the M4 selective Eastern Green Mamba venom MT3 (M4 pKb = 8.7, M1/M4 = 40-fold, M2/M4 ≥ 500-fold, M3/M4 500-fold, and M5/M4 ≥ 500-fold). Derivative 24, a compound with a high selectivity pattern as well, has been tested for in vivo efficacy. It was able to block the L-3,4-dihydroxyphenylalanine accumulation produced by CI-1017, an M1/M4 selective muscarinic agonist, in the mesolimbic region and striatum, which suggests that 24 is capable of crossing the blood-brain barrier and confirms the pharmacokinetic data obtained on this compound. This is evidence that suggests that agonist-induced increase in catecholamine synthesis observed in these regions is mediated by M4 receptors.
- B?hme, Thomas M.,Augelli-Szafran, Corinne E.,Hallak, Hussein,Pugsley, Thomas,Serpa, Kevin,Schwarz, Roy D.
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p. 3094 - 3102
(2007/10/03)
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