4.7 Article

The Role of Allylic Strain for Conformational Control in Medicinal Chemistry

相关参考文献

注意:仅列出部分参考文献,下载原文获取全部文献信息。
Article Chemistry, Medicinal

Synthetic Strategies for Improving Solubility: Optimization of Novel Pyrazolo[1,5-a]pyrimidine CFTR Activator That Ameliorates Dry Eye Disease

Bo Yi Kim et al.

Summary: Dry eye disease (DED) is a common ocular disease with limited treatment options. CFTR, a major chloride channel, may provide new therapeutic strategies for DED. This study optimized a CFTR activator, 16d, with suitable solubility for eye drop formulation. Topical instillation of 16d significantly enhanced tear secretion, improved corneal erosion, and reduced pro-inflammatory cytokines in DED mice.

JOURNAL OF MEDICINAL CHEMISTRY (2023)

Article Chemistry, Medicinal

Discovery of Dual TAF1-ATR Inhibitors and Ligand-Induced Structural Changes of the TAF1 Tandem Bromodomain

Rezaul Md Karim et al.

Summary: Bromodomains play a regulatory role in chromatin remodeling and gene transcription by recognizing acetylated lysines. TAF1, a protein containing Bromodomain, is a crucial component in the formation of preinitiation complex and cellular transcription. It also acts as a cofactor for oncogenic transcription factors and is involved in regulating the p53 tumor suppressor. Therefore, TAF1 could be a potential target for developing small molecule therapeutics for diseases associated with dysregulated transcription, such as cancer. The ATR kinase inhibitor AZD6738 and its analogues have been identified as effective inhibitors of TAF1, and their mechanism of action has been elucidated through crystallographic and small-angle X-ray scattering studies.

JOURNAL OF MEDICINAL CHEMISTRY (2022)

Article Chemistry, Organic

Synthesis and Structural Characterization of β-Turn Mimics Containing (Z)-Chloroalkene Dipeptide Isosteres

Yuki Kodama et al.

Summary: This study presents the synthetic, spectroscopic, crystallographic, and computational analysis of a series of peptidomimetics containing L-Xaa-D-Yaa-type (Z)-chloroalkene dipeptide isosteres (CADIs). It is found that the 1,3-allylic strain across the chloroalkene moiety induces hyperconjugative interactions, contributing significantly to the stabilization of beta-turn structures.

JOURNAL OF ORGANIC CHEMISTRY (2022)

Article Chemistry, Multidisciplinary

Modulating Conformational Preferences by Allylic Strain toward Improved Physical Properties and Binding Interactions

Hongtao Zhao

Summary: The preference for axial substituents over equatorial substituents in phenyl-1-piperidines and N-acylpiperidines was studied using the M06-2X level of theory. The results showed that axial substituents are modestly favored in phenyl-1-piperidines, while in N-acylpiperidines, the axial orientation is dictated by pseudoallylic strain. The study also investigated the equilibrium between twist-boat and chair conformations in N-acylpiperidines with a 2-substituent, finding that the twist-boat conformation is less favorable. Additionally, the three-dimensionality resulting from minimizing pseudoallylic strain was characterized and its implications in protein-ligand interactions were briefly reviewed.

ACS OMEGA (2022)

Article Chemistry, Medicinal

Surprising lipophilicity observations identify unexpected conformational effects

Matthew W. D. Perry et al.

Summary: Contrary to expectations, N-aryl pyrrolidinones (and isosteric imidazolinones and oxazolinones) have higher lipophilicity and lower solubility than corresponding piper-idinones (tetrahydropyrimidinones and oxazinones). The observed effects are driven by a subtle interplay of steric and electronic effects, resulting in different conformations for the two classes of compounds.

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS (2022)

Article Chemistry, Organic

Conformational Switch of Benzanilide Derivative Induced by Acid; Effect of Pentafluorobenzoyl Group

Ryu Yamasaki et al.

Summary: In this study, a series of pentafluorobenzoyl-based benzanilide compounds were designed and synthesized. It was found that the conformational ratio of these compounds in solution correlated linearly with the substituent on the anilide ring. Acid addition was able to switch one of the conformations.

JOURNAL OF ORGANIC CHEMISTRY (2022)

Article Chemistry, Multidisciplinary

Structural Basis of the Modulation of the Voltage-Gated Calcium Ion Channel Cav1.1 by Dihydropyridine Compounds**

Shuai Gao et al.

Summary: This study reports the structures of Ca(v)1.1 bound with different drugs, revealing the molecular basis for their effects. The structures show that amlodipine and nifedipine have different impacts on Ca(v)1.1, while the two enantiomers of Bay K8644 as agonists are insufficient to maintain the activated state of the channel.

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION (2021)

Article Chemistry, Medicinal

Large-Scale Analysis of Bioactive Ligand Conformational Strain Energy by Ab Initio Calculation

Jiahui Tong et al.

Summary: This study constructed a high-quality dataset of ligand-bound conformations and calculated ligand conformational strain energy (LCSE) at different levels. The LCSE was found to be correlated with several ligand properties and the summation of torsion strains is a good approximation for most cases.

JOURNAL OF CHEMICAL INFORMATION AND MODELING (2021)

Article Multidisciplinary Sciences

An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19

Dafydd R. Owen et al.

Summary: PF-07321332, an orally bioavailable SARS-CoV-2 main protease inhibitor, has been discovered with in vitro pan-human coronavirus antiviral activity and excellent off-target selectivity and in vivo safety profiles. This new drug has shown promise in countering the threat of COVID-19 with its oral activity and safety in clinical trials.

SCIENCE (2021)

Article Chemistry, Medicinal

Discovery of GLPG1972/S201086, a Potent, Selective, and Orally Bioavailable ADAMTS-5 Inhibitor for the Treatment of Osteoarthritis

Franck Brebion et al.

Summary: GLPG1972/S201086 is a potent and selective ADAMTS-5 inhibitor obtained through optimization of a promising hydantoin series. The compound has shown biochemical activity against rat and human ADAMTS-5, and demonstrated anticatabolic and anticatabolic activity.

JOURNAL OF MEDICINAL CHEMISTRY (2021)

Article Chemistry, Medicinal

Discovery of AZD8154, a Dual PI3Kγδ Inhibitor for the Treatment of Asthma

Matthew W. D. Perry et al.

Summary: Starting from previously described PI3K gamma inhibitors, exploration of structure-activity relationships led to the discovery of highly potent dual PI3K gamma delta inhibitors. The optimized compound, AZD8154, demonstrated efficacy in allergic asthma models and showed long duration of action in the lung with low systemic exposure and high selectivity against off-targets.

JOURNAL OF MEDICINAL CHEMISTRY (2021)

Article Chemistry, Medicinal

The Good, the Bad, and the Twisted Revisited: An Analysis of Ligand Geometry in Highly Resolved Protein-Ligand X-ray Structures

John W. Liebeschuetz

Summary: The analysis of rotatable bond geometry in high-resolution crystallographic protein-ligand complexes shows that unusual torsional geometry is rare in cases with good fit to electron density, but more prevalent in cases with imperfect fit. Multiple low-strain conformer bindings were observed in some cases, indicating the need for more robust crystallographic refinement methods.

JOURNAL OF MEDICINAL CHEMISTRY (2021)

Review Biotechnology & Applied Microbiology

PI3K inhibitors are finally coming of age

Bart Vanhaesebroeck et al.

Summary: Overactive PI3K is a frequently activated pathway in cancer, but therapeutic PI3K pathway inhibitors face challenges such as poor drug tolerance and resistance. Several targeted PI3K inhibitors have received regulatory approval, and their potential in cancer immunotherapy has been highlighted.

NATURE REVIEWS DRUG DISCOVERY (2021)

Article Chemistry, Medicinal

Comparison of Orexin 1 and Orexin 2 Ligand Binding Modes Using X-ray Crystallography and Computational Analysis

Mathieu Rappas et al.

JOURNAL OF MEDICINAL CHEMISTRY (2020)

Article Biochemistry & Molecular Biology

Human PLD structures enable drug design and characterization of isoenzyme selectivity

Claire M. Metrick et al.

NATURE CHEMICAL BIOLOGY (2020)

Review Chemistry, Multidisciplinary

Conformational Design Principles in Total Synthesis

Renzhi Chen et al.

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION (2020)

Article Multidisciplinary Sciences

The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity

Jude Canon et al.

NATURE (2019)

Article Chemistry, Medicinal

Ligand Desolvation Steers On-Rate and Impacts Drug Residence Time of Heat Shock Protein 90 (Hsp90) Inhibitors

Doris A. Schuetz et al.

JOURNAL OF MEDICINAL CHEMISTRY (2018)

Article Chemistry, Medicinal

Molecular Basis for Multiple Omapatrilat Binding Sites within the ACE C-Domain: Implications for Drug Design

Gyles E. Cozier et al.

JOURNAL OF MEDICINAL CHEMISTRY (2018)

Article Crystallography

Crystal structure of (S)-5-chloro-N-({2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]oxazolidin-5-yl}methyl)thiophene-2-carboxamide

Jie Shen et al.

ACTA CRYSTALLOGRAPHICA SECTION E-CRYSTALLOGRAPHIC COMMUNICATIONS (2018)

Review Chemistry, Multidisciplinary

From Peptides to Peptidomimetics: A Strategy Based on the Structural Features of Cyclopropane

Akira Mizuno et al.

CHEMISTRY-A EUROPEAN JOURNAL (2017)

Article Chemistry, Medicinal

Conformational control in structure-based drug design

Yajun Zheng et al.

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS (2017)

Article Chemistry, Medicinal

Nucleoside Phosphate and Phosphonate Prodrug Clinical Candidates

Peter J. Thornton et al.

JOURNAL OF MEDICINAL CHEMISTRY (2016)

Article Chemistry, Medicinal

Discovery of a Novel, Orally Efficacious Liver X Receptor (LXR) β Agonist

Yajun Zheng et al.

JOURNAL OF MEDICINAL CHEMISTRY (2016)

Article Chemistry, Medicinal

Discovery of novel pyrazole-containing benzamides as potent ROR gamma inverse agonists

Tao Wang et al.

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS (2015)

Article Chemistry, Medicinal

Discovery of biaryl carboxylamides as potent RORγ inverse agonists

Jianhua Chao et al.

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS (2015)

Article Chemistry, Medicinal

Fluorine in Drug Design: A Case Study with Fluoroanisoles

Li Xing et al.

CHEMMEDCHEM (2015)

Article Chemistry, Medicinal

Discovery of AZD3147: A Potent, Selective Dual Inhibitor of mTORC1 and mTORC2

Kurt G. Pike et al.

JOURNAL OF MEDICINAL CHEMISTRY (2015)

Article Chemistry, Medicinal

Applications of Fluorine in Medicinal Chemistry

Eric P. Gillis et al.

JOURNAL OF MEDICINAL CHEMISTRY (2015)

Article Chemistry, Medicinal

Structure-Based Drug Design of Novel Potent and Selective Tetrahydropyrazolo[1,5-a]pyrazines as ATR Inhibitors

Paul A. Barsanti et al.

ACS MEDICINAL CHEMISTRY LETTERS (2015)

Review Chemistry, Medicinal

Conformational restriction: an effective tactic in 'follow-on'-based drug discovery

Zengjun Fang et al.

FUTURE MEDICINAL CHEMISTRY (2014)

Article Biochemistry & Molecular Biology

Allosteric Competitive Inhibitors of the Glucose-1-phosphate Thymidylyltransferase (RmlA) from Pseudomonas aeruginosa

Magnus S. Alphey et al.

ACS CHEMICAL BIOLOGY (2013)

Review Chemistry, Multidisciplinary

Profound Methyl Effects in Drug Discovery and a Call for New C-H Methylation Reactions

Heike Schoenherr et al.

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION (2013)

Article Chemistry, Medicinal

Torsion Angle Preferences in Druglike Chemical Space: A Comprehensive Guide

Christin Schaerfer et al.

JOURNAL OF MEDICINAL CHEMISTRY (2013)

Review Biotechnology & Applied Microbiology

Advances in the development of nucleoside and nucleotide analogues for cancer and viral diseases

Lars Petter Jordheim et al.

NATURE REVIEWS DRUG DISCOVERY (2013)

Article Biochemistry & Molecular Biology

A Potent and Selective S1P1 Antagonist with Efficacy in Experimental Autoimmune Encephalomyelitis

Jean Quancard et al.

CHEMISTRY & BIOLOGY (2012)

Article Chemistry, Multidisciplinary

Ideal Molecular Conformation versus Crystal Site Symmetry

Robert A. Pascal et al.

CRYSTAL GROWTH & DESIGN (2012)

Article Chemistry, Multidisciplinary

Systematic conformational bias in small-molecule crystal structures is rare and explicable

Aurora J. Cruz-Cabeza et al.

CRYSTENGCOMM (2012)

Article Chemistry, Medicinal

Methyl Effects on Protein-Ligand Binding

Cheryl S. Leung et al.

JOURNAL OF MEDICINAL CHEMISTRY (2012)

Review Biochemistry & Molecular Biology

An Evaluation of Peptide-Bond Isosteres

Amit Choudhary et al.

CHEMBIOCHEM (2011)

Review Chemistry, Multidisciplinary

Phospholipase D: Enzymology, Functionality, and Chemical Modulation

Paige E. Selvy et al.

CHEMICAL REVIEWS (2011)

Article Chemistry, Medicinal

Synopsis of Some Recent Tactical Application of Bioisosteres in Drug Design

Nicholas A. Meanwell

JOURNAL OF MEDICINAL CHEMISTRY (2011)

Article Chemistry, Medicinal

Discovery of AMG 369, a Thiazolo[5,4-b]pyridine Agonist of S1P1 and S1P5

Victor J. Cee et al.

ACS MEDICINAL CHEMISTRY LETTERS (2011)

Article Chemistry, Multidisciplinary

A Graphical Journey of Innovative Organic Architectures That Have Improved Our Lives

Nicholas A. McGrath et al.

JOURNAL OF CHEMICAL EDUCATION (2010)

Article Chemistry, Medicinal

A Medicinal Chemist's Guide to Molecular Interactions

Caterina Bissantz et al.

JOURNAL OF MEDICINAL CHEMISTRY (2010)

Article Multidisciplinary Sciences

Retroviral intasome assembly and inhibition of DNA strand transfer

Stephen Hare et al.

NATURE (2010)

Article Biochemistry & Molecular Biology

The p110δ structure: mechanisms for selectivity and potency of new PI(3)K inhibitors

Alex Berndt et al.

NATURE CHEMICAL BIOLOGY (2010)

Review Biotechnology & Applied Microbiology

Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis

Volker Brinkmann et al.

NATURE REVIEWS DRUG DISCOVERY (2010)

Article Biochemistry & Molecular Biology

Phosphatidic acid signaling to mTOR: Signals for the survival of human cancer cells

David A. Foster

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS (2009)

Article Chemistry, Medicinal

Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success

Frank Lovering et al.

JOURNAL OF MEDICINAL CHEMISTRY (2009)

Article Biochemistry & Molecular Biology

Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness

Sarah A. Scott et al.

NATURE CHEMICAL BIOLOGY (2009)

Article Chemistry, Organic

Synthesis and conformational analysis of α,α-difluoroalkyl heteroaryl ethers

Daniel B. Horne et al.

TETRAHEDRON LETTERS (2009)

Review Chemistry, Medicinal

Small molecule conformational preferences derived from crystal structure data. A medicinal chemistry focused analysis

Ken A. Brameld et al.

JOURNAL OF CHEMICAL INFORMATION AND MODELING (2008)

Review Immunology

Finding a way out: lymphocyte egress from lymphoid organs

Susan R. Schwab et al.

NATURE IMMUNOLOGY (2007)

Article Chemistry, Multidisciplinary

Cyclopropyl conjugation and ketyl anions: When do things begin to fall apart?

J. M. Tanko et al.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY (2007)

Article Chemistry, Organic

Convergent approach to (E)-alkene and cyclopropane peptide isosteres

P Wipf et al.

ORGANIC LETTERS (2005)

Article Chemistry, Multidisciplinary

New software for searching the Cambridge Structural Database and visualizing crystal structures

IJ Bruno et al.

ACTA CRYSTALLOGRAPHICA SECTION B-STRUCTURAL SCIENCE CRYSTAL ENGINEERING AND MATERIALS (2002)

Article Chemistry, Medicinal

Structure-based design of novel potent nonpeptide thrombin inhibitors

NH Hauel et al.

JOURNAL OF MEDICINAL CHEMISTRY (2002)

Review Chemistry, Organic

Can we predict the conformational preference of amides?

M Avalos et al.

JOURNAL OF ORGANIC CHEMISTRY (2001)

Article Chemistry, Multidisciplinary

Molecular mechanics calculations on carbonyl compounds. II. Open-chain ketones

CH Langley et al.

JOURNAL OF COMPUTATIONAL CHEMISTRY (2001)

Article Multidisciplinary Sciences

Hyperconjugation not steric repulsion leads to the staggered structure of ethane

V Pophristic et al.

NATURE (2001)

Article Multidisciplinary Sciences

Structural mechanism for statin inhibition of HMG-CoA reductase

ES Istvan et al.

SCIENCE (2001)

Article Biochemistry & Molecular Biology

Participation of the beta-hydroxyketone part for potent cytotoxicity of callystatin A, a spongean polyketide

N Murakami et al.

BIOORGANIC & MEDICINAL CHEMISTRY (2001)