Lucja Orzechowski - Academia.edu (original) (raw)
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Papers by Lucja Orzechowski
Disclosed herein are compounds, including compounds hav ing the structure of Formula (A), (B), (C... more Disclosed herein are compounds, including compounds hav ing the structure of Formula (A), (B), (C), and (D), as described in further detail herein, that form covalent bonds with Bruton's tyrosine kinase (Btk). Also described are irre versible inhibitors of Btk. Methods for the preparation of the compounds are disclosed. Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the Btkinhibitors are disclosed, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions.
Bioorganic & medicinal …, 2008
This paper describes the lead optimization of a new series of potent, selective, orally bioavaila... more This paper describes the lead optimization of a new series of potent, selective, orally bioavailable, brain-penetrant MCH-1 receptor antagonists. A major focus of the work was to achieve a selectivity profile appropriate for in vivo efficacy studies and safety.
Bioorganic & Medicinal Chemistry Letters, 2016
Bioconjugate chemistry, Jan 19, 2016
Bioconjugate chemistry, Jan 29, 2015
Complex mixtures of DNA encoded small-molecules may be readily interrogated via high throughput s... more Complex mixtures of DNA encoded small-molecules may be readily interrogated via high throughput sequencing. These DNA encoded libraries (DELs) are commonly used to discover molecules which interact with pharmaceutically relevant proteins. The chemical diversity displayed by the library is key to successful discovery of potent, novel, and drug-like chemical matter. The small-molecule moieties of DELs are generally synthesized though a multi-step process, and each chemical step is accomplished while simultaneously attached to an encoding DNA oligomer. Hence, library chemical diversity is often limited to DNA compatible synthetic reactions. Herein protocols for twenty-four reactions are provided that have been optimized for high-throughput production of DELs. These protocols detail the multi-step synthesis of benzimidazoles, imidazolidinones, quinazolinones, isoindolinones, thiazoles, and imidazopyridines. Additionally, protocols are provided for a diverse range of useful chemical reac...
![Research paper thumbnail of 7-Phenyl-pyrido[2,3-d]pyrimidine-2,4-diamines: Novel and highly selective protein tyrosine phosphatase 1B inhibitors](https://attachments.academia-assets.com/50824469/thumbnails/1.jpg)
](Bioorganic & Medicinal Chemistry Letters, 2012
High throughput screening of the Roche compound collection led to the identification of diaminopy... more High throughput screening of the Roche compound collection led to the identification of diaminopyrroloquinazoline series as a novel class of PTP1B inhibitors. Structural modification of diaminopyrroloquinazoline series resulted in pyrido [2,3-d]pyrimidine-2,4-diamine series which was further optimized to give compounds 5 and 24 as potent, selective (except T-cell phosphatase) PTP1B inhibitors with good mouse PK properties.
Anti-Cancer Drugs, 2002
Ro 41-4439, a phenyl-pyridine-2-carboxylic acid derivative, was identified by a cell-based screen... more Ro 41-4439, a phenyl-pyridine-2-carboxylic acid derivative, was identified by a cell-based screening approach that exploits the differences between normal and cancer cells in their sensitivity to cytotoxic agents. This compound showed low micromolar antiproliferative activity and cytotoxicity against a broad panel of human cancer cell lines in vitro, and over 10-fold selectivity to cancer cells when tested in parallel with a panel of proliferating normal human cells. Cytotoxicity of Ro 41-4439 is due to arrest of cell cycle progression in mitosis followed by induction of apoptosis. Four-week treatment of nude mice bearing established mammary tumor xenografts (MDA-MB-435) with well-tolerated doses of the compound showed 73% inhibition of tumor growth. Limited exploration of structure-activity relationships involving side chain length, and aryl and pyridine rings allowed for the identification of more potent analogs.
Journal of Medicinal Chemistry, 2000
Molecular features of ligand binding to MHC class II HLA-DR molecules have been elucidated throug... more Molecular features of ligand binding to MHC class II HLA-DR molecules have been elucidated through a combination of peptide structure-activity studies and structure-based drug design, resulting in analogues with nanomolar affinity in binding assays. Stabilization of lead compounds against cathepsin B cleavage by N-methylation of noncritical backbone NH groups or by dipeptide mimetic substitutions has generated analogues that compete effectively against protein antigens in cellular assays, resulting in inhibition of T-cell proliferation. Crystal structures of four ternary complexes of different peptide mimetics with the rheumatoid arthritis-linked MHC DRB10401 and the bacterial superantigen SEB have been obtained. Peptide-sugar hybrids have also been identified using a structure-based design approach in which the sugar residue replaces a dipeptide. These studies illustrate the complementary roles played by phage display library methods, peptide analogue SAR, peptide mimetics substitutions, and structure-based drug design in the discovery of inhibitors of antigen presentation by MHC class II HLA-DR molecules.
Disclosed herein are compounds, including compounds hav ing the structure of Formula (A), (B), (C... more Disclosed herein are compounds, including compounds hav ing the structure of Formula (A), (B), (C), and (D), as described in further detail herein, that form covalent bonds with Bruton's tyrosine kinase (Btk). Also described are irre versible inhibitors of Btk. Methods for the preparation of the compounds are disclosed. Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the Btkinhibitors are disclosed, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions.
Bioorganic & medicinal …, 2008
This paper describes the lead optimization of a new series of potent, selective, orally bioavaila... more This paper describes the lead optimization of a new series of potent, selective, orally bioavailable, brain-penetrant MCH-1 receptor antagonists. A major focus of the work was to achieve a selectivity profile appropriate for in vivo efficacy studies and safety.
Bioorganic & Medicinal Chemistry Letters, 2016
Bioconjugate chemistry, Jan 19, 2016
Bioconjugate chemistry, Jan 29, 2015
Complex mixtures of DNA encoded small-molecules may be readily interrogated via high throughput s... more Complex mixtures of DNA encoded small-molecules may be readily interrogated via high throughput sequencing. These DNA encoded libraries (DELs) are commonly used to discover molecules which interact with pharmaceutically relevant proteins. The chemical diversity displayed by the library is key to successful discovery of potent, novel, and drug-like chemical matter. The small-molecule moieties of DELs are generally synthesized though a multi-step process, and each chemical step is accomplished while simultaneously attached to an encoding DNA oligomer. Hence, library chemical diversity is often limited to DNA compatible synthetic reactions. Herein protocols for twenty-four reactions are provided that have been optimized for high-throughput production of DELs. These protocols detail the multi-step synthesis of benzimidazoles, imidazolidinones, quinazolinones, isoindolinones, thiazoles, and imidazopyridines. Additionally, protocols are provided for a diverse range of useful chemical reac...
Bioorganic & Medicinal Chemistry Letters, 2012
High throughput screening of the Roche compound collection led to the identification of diaminopy... more High throughput screening of the Roche compound collection led to the identification of diaminopyrroloquinazoline series as a novel class of PTP1B inhibitors. Structural modification of diaminopyrroloquinazoline series resulted in pyrido [2,3-d]pyrimidine-2,4-diamine series which was further optimized to give compounds 5 and 24 as potent, selective (except T-cell phosphatase) PTP1B inhibitors with good mouse PK properties.
Anti-Cancer Drugs, 2002
Ro 41-4439, a phenyl-pyridine-2-carboxylic acid derivative, was identified by a cell-based screen... more Ro 41-4439, a phenyl-pyridine-2-carboxylic acid derivative, was identified by a cell-based screening approach that exploits the differences between normal and cancer cells in their sensitivity to cytotoxic agents. This compound showed low micromolar antiproliferative activity and cytotoxicity against a broad panel of human cancer cell lines in vitro, and over 10-fold selectivity to cancer cells when tested in parallel with a panel of proliferating normal human cells. Cytotoxicity of Ro 41-4439 is due to arrest of cell cycle progression in mitosis followed by induction of apoptosis. Four-week treatment of nude mice bearing established mammary tumor xenografts (MDA-MB-435) with well-tolerated doses of the compound showed 73% inhibition of tumor growth. Limited exploration of structure-activity relationships involving side chain length, and aryl and pyridine rings allowed for the identification of more potent analogs.
Journal of Medicinal Chemistry, 2000
Molecular features of ligand binding to MHC class II HLA-DR molecules have been elucidated throug... more Molecular features of ligand binding to MHC class II HLA-DR molecules have been elucidated through a combination of peptide structure-activity studies and structure-based drug design, resulting in analogues with nanomolar affinity in binding assays. Stabilization of lead compounds against cathepsin B cleavage by N-methylation of noncritical backbone NH groups or by dipeptide mimetic substitutions has generated analogues that compete effectively against protein antigens in cellular assays, resulting in inhibition of T-cell proliferation. Crystal structures of four ternary complexes of different peptide mimetics with the rheumatoid arthritis-linked MHC DRB10401 and the bacterial superantigen SEB have been obtained. Peptide-sugar hybrids have also been identified using a structure-based design approach in which the sugar residue replaces a dipeptide. These studies illustrate the complementary roles played by phage display library methods, peptide analogue SAR, peptide mimetics substitutions, and structure-based drug design in the discovery of inhibitors of antigen presentation by MHC class II HLA-DR molecules.