Natalie Dales - Academia.edu (original) (raw)

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Papers by Natalie Dales

Research paper thumbnail of Heterocyclic inhibitors of stearoyl-CoA desaturase

Research paper thumbnail of Ace-2 modulating compounds and use thereof

Research paper thumbnail of Chk-1 inhibitors

Research paper thumbnail of SCD1 inhibitors triazole and tetrazole compounds

Research paper thumbnail of ACE-2 Inhibiting Compounds and Methods of Use Thereof

Research paper thumbnail of Heterocyclic organic compounds

Research paper thumbnail of Pharmacological Inhibition of Stearoyl CoA Desaturase 1 in the Skin Induces Atrophy of the Sebaceous Glands

Research paper thumbnail of Spiro Derivatives for the Modulation of Stearoyl-Coa Desaturase

Research paper thumbnail of Heterocyclic compounds suitable for the treatment of diseases related to elevated lipid levels

Research paper thumbnail of Synthesis of (3R)-Amino-(2S)-Hydroxy Amino Acids for Inhibition of Methionine Aminopeptidase-1

Syn Commun, 1998

Stacy J. Keding,a Natalie A. Dales: Sejin Lim,a Danielle Beaulieu: Daniel H. Richa* ... &... more Stacy J. Keding,a Natalie A. Dales: Sejin Lim,a Danielle Beaulieu: Daniel H. Richa* ... 'Departnzent of' Chemistry and School of Pharmacy, University of Wisconsin-Madison, 425 North Charter Street, Madison, WI 53 706. hBristol-Myers Squibb Pharmaceutical Research Institute, ...

Research paper thumbnail of Lactam Compounds Useful as Protein Kinase Inhibitors

Research paper thumbnail of ACE-2 modulating compounds and methods of use thereof

Research paper thumbnail of ChemInform Abstract: Synthesis of (3R)-Amino-(2S)-hydroxy Amino Acids for Inhibition of Methionine Aminopeptidase-1

ChemInform, 1999

Synthesis of (3R)-Amino-(2S)-hydroxy Amino Acids for Inhibition of Methionine Aminopeptidase-1.

Research paper thumbnail of Transformation of Peptides into Non-Peptides. Synthesis of Computer-Generated Enzyme Inhibitors

CHIMIA International Journal for Chemistry

ABSTRACT

Research paper thumbnail of Synthesis of (3R)-Amino-(2S)-Hydroxy Amino Acids for Inhibition of Methionine Aminopeptidase-1

Synthetic Communications, 1998

Stacy J. Keding,a Natalie A. Dales: Sejin Lim,a Danielle Beaulieu: Daniel H. Richa* ... &... more Stacy J. Keding,a Natalie A. Dales: Sejin Lim,a Danielle Beaulieu: Daniel H. Richa* ... 'Departnzent of' Chemistry and School of Pharmacy, University of Wisconsin-Madison, 425 North Charter Street, Madison, WI 53 706. hBristol-Myers Squibb Pharmaceutical Research Institute, ...

Research paper thumbnail of Substrate-Based Design of the First Class of Angiotensin-Converting Enzyme-Related Carboxypeptidase (ACE2) Inhibitors

Journal of the American Chemical Society, 2002

Research paper thumbnail of Pharmacological Inhibition of Stearoyl CoA Desaturase in the Skin Induces Atrophy of the Sebaceous Glands

Journal of Investigative Dermatology, 2013

Research paper thumbnail of ACE2 X-Ray Structures Reveal a Large Hinge-bending Motion Important for Inhibitor Binding and Catalysis

Journal of Biological Chemistry, 2004

The angiotensin-converting enzyme (ACE)-related carboxypeptidase, ACE2, is a type I integral memb... more The angiotensin-converting enzyme (ACE)-related carboxypeptidase, ACE2, is a type I integral membrane protein of 805 amino acids that contains one HEXXH ؉ E zincbinding consensus sequence. ACE2 has been implicated in the regulation of heart function and also as a functional receptor for the coronavirus that causes the severe acute respiratory syndrome (SARS). To gain further insights into this enzyme, the first crystal structures of the native and inhibitor-bound forms of the ACE2 extracellular domains were solved to 2.2-and 3.0-Å resolution, respectively. Comparison of these structures revealed a large inhibitor-dependent hinge-bending movement of one catalytic subdomain relative to the other (ϳ16°) that brings important residues into position for catalysis. The potent inhibitor

Research paper thumbnail of Enzymatic Characterization of the Pancreatic Islet-specific Glucose-6-Phosphatase-related Protein (IGRP)

Journal of Biological Chemistry, 2004

Research paper thumbnail of Discovery of thiazolylpyridinone SCD1 inhibitors with preferential liver distribution and reduced mechanism-based adverse effects

Bioorganic & Medicinal Chemistry Letters, 2014

We discovered a series of novel and potent thiazolylpyridinone-based SCD1 inhibitors based on a 2... more We discovered a series of novel and potent thiazolylpyridinone-based SCD1 inhibitors based on a 2-aminothiazole HTS hit by replacing the amide bond with a pyridinone moiety. Compound 19 demonstrated good potency against SCD1 in vitro and in vivo. The mouse liver microsomal SCD1 in vitro potency for 19 was improved by more than 240-fold compared to the original HTS hit. Furthermore, 19 demonstrated a dose-dependent reduction of plasma desaturation index with an ED50 of 6.3 mg/kg. Compound 19 demonstrated high liver to plasma and liver to eyelid exposures, indicating preferential liver distribution. The preliminary toxicology study with compound 19 did not demonstrate adverse effects related to SCD1 inhibition, suggesting a wide safety margin with respect to other known SCD1 inhibitors with wider distribution profiles.

Research paper thumbnail of Heterocyclic inhibitors of stearoyl-CoA desaturase

Research paper thumbnail of Ace-2 modulating compounds and use thereof

Research paper thumbnail of Chk-1 inhibitors

Research paper thumbnail of SCD1 inhibitors triazole and tetrazole compounds

Research paper thumbnail of ACE-2 Inhibiting Compounds and Methods of Use Thereof

Research paper thumbnail of Heterocyclic organic compounds

Research paper thumbnail of Pharmacological Inhibition of Stearoyl CoA Desaturase 1 in the Skin Induces Atrophy of the Sebaceous Glands

Research paper thumbnail of Spiro Derivatives for the Modulation of Stearoyl-Coa Desaturase

Research paper thumbnail of Heterocyclic compounds suitable for the treatment of diseases related to elevated lipid levels

Research paper thumbnail of Synthesis of (3R)-Amino-(2S)-Hydroxy Amino Acids for Inhibition of Methionine Aminopeptidase-1

Syn Commun, 1998

Stacy J. Keding,a Natalie A. Dales: Sejin Lim,a Danielle Beaulieu: Daniel H. Richa* ... &... more Stacy J. Keding,a Natalie A. Dales: Sejin Lim,a Danielle Beaulieu: Daniel H. Richa* ... 'Departnzent of' Chemistry and School of Pharmacy, University of Wisconsin-Madison, 425 North Charter Street, Madison, WI 53 706. hBristol-Myers Squibb Pharmaceutical Research Institute, ...

Research paper thumbnail of Lactam Compounds Useful as Protein Kinase Inhibitors

Research paper thumbnail of ACE-2 modulating compounds and methods of use thereof

Research paper thumbnail of ChemInform Abstract: Synthesis of (3R)-Amino-(2S)-hydroxy Amino Acids for Inhibition of Methionine Aminopeptidase-1

ChemInform, 1999

Synthesis of (3R)-Amino-(2S)-hydroxy Amino Acids for Inhibition of Methionine Aminopeptidase-1.

Research paper thumbnail of Transformation of Peptides into Non-Peptides. Synthesis of Computer-Generated Enzyme Inhibitors

CHIMIA International Journal for Chemistry

ABSTRACT

Research paper thumbnail of Synthesis of (3R)-Amino-(2S)-Hydroxy Amino Acids for Inhibition of Methionine Aminopeptidase-1

Synthetic Communications, 1998

Stacy J. Keding,a Natalie A. Dales: Sejin Lim,a Danielle Beaulieu: Daniel H. Richa* ... &... more Stacy J. Keding,a Natalie A. Dales: Sejin Lim,a Danielle Beaulieu: Daniel H. Richa* ... 'Departnzent of' Chemistry and School of Pharmacy, University of Wisconsin-Madison, 425 North Charter Street, Madison, WI 53 706. hBristol-Myers Squibb Pharmaceutical Research Institute, ...

Research paper thumbnail of Substrate-Based Design of the First Class of Angiotensin-Converting Enzyme-Related Carboxypeptidase (ACE2) Inhibitors

Journal of the American Chemical Society, 2002

Research paper thumbnail of Pharmacological Inhibition of Stearoyl CoA Desaturase in the Skin Induces Atrophy of the Sebaceous Glands

Journal of Investigative Dermatology, 2013

Research paper thumbnail of ACE2 X-Ray Structures Reveal a Large Hinge-bending Motion Important for Inhibitor Binding and Catalysis

Journal of Biological Chemistry, 2004

The angiotensin-converting enzyme (ACE)-related carboxypeptidase, ACE2, is a type I integral memb... more The angiotensin-converting enzyme (ACE)-related carboxypeptidase, ACE2, is a type I integral membrane protein of 805 amino acids that contains one HEXXH ؉ E zincbinding consensus sequence. ACE2 has been implicated in the regulation of heart function and also as a functional receptor for the coronavirus that causes the severe acute respiratory syndrome (SARS). To gain further insights into this enzyme, the first crystal structures of the native and inhibitor-bound forms of the ACE2 extracellular domains were solved to 2.2-and 3.0-Å resolution, respectively. Comparison of these structures revealed a large inhibitor-dependent hinge-bending movement of one catalytic subdomain relative to the other (ϳ16°) that brings important residues into position for catalysis. The potent inhibitor

Research paper thumbnail of Enzymatic Characterization of the Pancreatic Islet-specific Glucose-6-Phosphatase-related Protein (IGRP)

Journal of Biological Chemistry, 2004

Research paper thumbnail of Discovery of thiazolylpyridinone SCD1 inhibitors with preferential liver distribution and reduced mechanism-based adverse effects

Bioorganic & Medicinal Chemistry Letters, 2014

We discovered a series of novel and potent thiazolylpyridinone-based SCD1 inhibitors based on a 2... more We discovered a series of novel and potent thiazolylpyridinone-based SCD1 inhibitors based on a 2-aminothiazole HTS hit by replacing the amide bond with a pyridinone moiety. Compound 19 demonstrated good potency against SCD1 in vitro and in vivo. The mouse liver microsomal SCD1 in vitro potency for 19 was improved by more than 240-fold compared to the original HTS hit. Furthermore, 19 demonstrated a dose-dependent reduction of plasma desaturation index with an ED50 of 6.3 mg/kg. Compound 19 demonstrated high liver to plasma and liver to eyelid exposures, indicating preferential liver distribution. The preliminary toxicology study with compound 19 did not demonstrate adverse effects related to SCD1 inhibition, suggesting a wide safety margin with respect to other known SCD1 inhibitors with wider distribution profiles.

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