- Discovery of silyl proline containing HCV NS5A inhibitors with pan-genotype activity: SAR development
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HCV NS5A inhibitors have shown impressive in vitro potency profiles in HCV replicon assays thus making them attractive components for inclusion in an all oral fixed dose combination treatment regimen. Herein we describe the research efforts that led to the discovery of silyl proline containing HCV NS5A inhibitors such as 7e and 8a with pan-genotype activity profile and acceptable pharmacokinetic properties.
- Nair, Anilkumar G.,Zeng, Qingbei,Selyutin, Oleg,Rosenblum, Stuart B.,Jiang, Yueheng,Yang, De-Yi,Keertikar, Kerry,Zhou, Guowei,Dwyer, Michael P.,Kim, Seong Heon,Shankar, Bandarpalle,Yu, Wensheng,Tong, Ling,Chen, Lei,Mazzola, Robert,Caldwell, John,Tang, Haiqun,Allard, Melissa L.,Buckle, Ronald N.,Gauuan, Polivina Jolicia F.,Holst, Christian L.,Martin, Gregory S.,Naicker, Kannan P.,Vellekoop, Samuel,Agrawal, Sony,Liu, Rong,Kong, Rong,Ingravallo, Paul,Xia, Ellen,Zhai, Ying,Nomeir, Amin,Kozlowski, Joseph A.
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- Silaproline helical mimetics selectively form an all-trans PPII helix
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The polyproline II helix (PPII) is increasingly recognized as an important element in peptide and protein structures. The discovery of pertinent PPII peptidomimetics is of great interest to tune physical properties of the targeted structure. A series of silaproline oligomers from dimer to pentamer were synthesized. CD studies, NMR spectroscopy and molecular modeling revealed that the ribbon preferentially populates the polyproline type II secondary structure in both [D]chloroform and [D4]MeOH. The characteristics of this new lipophilic PPII-like helix were determined.
- Martin, Charlotte,Legr, Baptiste,Lebrun, Aurlien,Berthomieu, Dorothe,Martinez, Jean,Cavelier, Florine
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- COMPOUNDS FOR THE TREATMENT OF MEDICAL DISORDERS
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Compounds, methods of use, and processes for making inhibitors of complement Factor D comprising Formula (I), or a pharmaceutically acceptable salt or composition thereof The inhibitors described herein target Factor D and inhibit or regulate the complement cascade. The inhibitors of Factor D described herein reduce the excessive activation of complement.
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Paragraph 0538
(2017/03/14)
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- ARYL, HETEROARYL, AND HETEROCYCLIC COMPOUNDS FOR TREATMENT OF MEDICAL DISORDERS
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Compounds, methods of use, and processes for making inhibitors of complement Factor D comprising Formula I, or a pharmaceutically acceptable salt or composition thereof wherein R12 or R13 on the A group is an aryl, heteroaryl or heterocycle (R32) are provided. The inhibitors of Factor D described herein reduce the excessive activation of complement.
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Paragraph 0801
(2017/03/14)
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- Asymmetric Synthesis of N-Boc-(R)-Silaproline via Rh-Catalyzed Intramolecular Hydrosilylation of Dehydroalanine and Continuous Flow N-Alkylation
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An asymmetric synthesis of a silicon-containing proline surrogate, N-Boc-(R)-silaproline (1), is described. Starting from N-Boc-dehydroalanine ester, deprotonation, followed by N-alkylation with chloromethyldimethylsilane under flow conditions, afforded the N-alkylated product 8 in 91% yield. An unprecedented enantioselective (NBD)2RhBF4/Josiphos 404-1 catalyzed 5-endo-trig hydrosilylation afforded the silaproline ester in 85-90% yield and >95% ee. Subsequent saponification and salt formation upgraded 1 to >99% ee.
- Chung, John Y. L.,Shevlin, Michael,Klapars, Artis,Journet, Michel
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supporting information
p. 1812 - 1815
(2016/05/19)
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- IAP ANTAGONISTS
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There are disclosed compounds that modulate the activity of inhibitors of apoptosis (lAPs), pharmaceutical compositions containing said compounds and methods of treating proliferative disorders and disorders of dysregulated apoptosis, such as cancer, utilizing the compounds of the invention.
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Paragraph 00133; 00137
(2014/02/15)
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- HEPATITIS C VIRUS INHIBITORS
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The invention provides compounds of formulas (I) or (II): wherein the variables are defined in the specification, or a pharmaceutically-acceptable salt thereof, that are inhibitors of replication of the hepatitis C virus. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat hepatitis C viral infections, and processes and intermediates useful for preparing such compounds.
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Paragraph 0269
(2013/11/06)
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- SILYL-CONTAINING HETEROCYCLIC COMPOUNDS AND METHODS OF USE THEREOF FOR THE TREATMENT OF VIRAL DISEASES
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The present invention relates to novel Silyl-Containing Heterocyclic Compounds of Formula (I): and pharmaceutically acceptable salts thereof, wherein A, B, C, D, E, F and L are as defined herein. The present invention also relates to compositions comprising at least one Silyl-Containing Heterocyclic Compound, and methods of using the Silyl-Containing Heterocyclic Compounds for treating or preventing HCV infection in a patient.
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Page/Page column 75
(2013/03/28)
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- SILYL-CONTAINING HETEROCYCLIC COMPOUNDS AND METHODS OF USE THEREOF FOR THE TREATMENT OF VIRAL DISEASES
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The present invention relates to novel Silyl-Containing Heterocyclic Compounds of Formula (I): (I) and pharmaceutically acceptable salts thereof, wherein A, B, C, D and R2 are as defined herein. The present invention also relates to compositions comprising at least one Silyl-Containing Heterocyclic Compound, and methods of using the Silyl-Containing Heterocyclic Compounds for treating or preventing HCV infection in a patient.
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Page/Page column 71
(2013/03/28)
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- TETRACYCLIC INDOLE DERIVATIVES FOR TREATING HEPATITIS C VIRUS INFECTION
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Tetracyclic indole derivatives of formula (I), pharmaceutically acceptable salts and the pharmaceutical compositions thereof are provided, wherein A, A', G, R1, R15, U, V, V, W, W, X, X', Y, Y' are as defined in the invention. Use of these derivatives for treating hepatitis C virus (HCV) infection is also provided.
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Page/Page column 115
(2012/04/17)
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- TETRACYCLIC XANTHENE DERIVATIVES AND METHODS OF USE THEREOF FOR THE TREATMENT OF VIRAL DISEASES
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The present invention relates to novel Tetracyclic Xanthene Derivatives of Formula (I) and pharmaceutically acceptable salts thereof, wherein A, Y1, Y2, Z, Ra, Rb, R1a, R1b and R2 are as defined herein. The present invention also relates to compositions comprising at least one Tetracyclic Xanthene Derivative, and methods of using the Tetracyclic Xanthene Derivatives for treating or preventing HCV infection in a patient.
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Page/Page column 43
(2012/10/07)
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- TETRACYCLIC XANTHENE DERIVATIVES AND METHODS OF USE THEREOF FOR TREATMENT OF VIRAL DISEASES
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The present invention discloses tetracyclic xanthene derivatives of Formula (I) and pharmaceutically acceptable salts thereof, wherein A, Y1, Y2, Z, Ra, Rb, R1a, R1b, and R2 are as defined herein. The present invention also discloses compositions comprising at least one tetracyclic xanthene derivative, and methods of using the tetracyclic xanthene derivatives for treating or preventing HCV infection in a patient.
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Page/Page column 62
(2012/10/07)
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- Synthesis of silaproline, a new proline surrogate
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The asymmetric synthesis of a new proline surrogate, incorporating the dimethylsilyl group at position 4 of proline using Schollkopf's bis-lactim ether method, is described.
- Vivet, Bertrand,Cavelier, Florine,Martinez, Jean
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p. 807 - 811
(2007/10/03)
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