Abstract
The structure-activity relationships of azetidine-based DPP IV inhibitors will be discussed in detail in the following review. The azetidine-based DPP IV inhibitors can be divided into three main subtypes, the 2-cyanoazetidines, 3-fluoroazetidines and 2-ketoazetidines. These subtypes have been explored and structure-activity relationships have been established by several groups. Several compounds within each of these subtypes display sub micromolar potency against DPP IV. The most potent cyanoazetidines and ketoazetidines have large, hydrophobic amino acid groups bound to the azetidine nitrogen and display activities below 100nM. DPP IV inhibition is not sensitive to stereochemistry at the 2- position as both 2-(R)- and 2-(S)-cyano and -keto azetidines display similar inhibitory potencies. While these “warhead”- based cyano- and ketoazetidines have the potential for covalent, bond-forming inhibition, they can also react to internally cyclize into inactive ketopiperazines and dihydroketopyrazine. Thus, chemical instability was also explored for compounds in these two subtypes and certain members of the cyanoazetidine series display aqueous stability comparable to the closely related cyanopyrrolidines. Select 3-fluoroazetidines also display inhibitory potencies below 1μM without the propensity for cyclization and chemical instability associated with the other subseries.
Keywords: Pyrrolidine Based DPP IV Inhibitors, ketone-based DPP IV inhibitors, Cyanopyrrolidine, fluoroazetidines, ketopyrrolidines
Current Topics in Medicinal Chemistry
Title: Azetidine-Based Inhibitors of Dipeptidyl Peptidase IV (DPP IV)
Volume: 7 Issue: 6
Author(s): Dana Ferraris, Sergei Belyakov, Weixing Li, Eddie Oliver, Yao-Sen Ko, David Calvin, Susan Lautar, Bert Thomas and Camilo Rojas
Affiliation:
Keywords: Pyrrolidine Based DPP IV Inhibitors, ketone-based DPP IV inhibitors, Cyanopyrrolidine, fluoroazetidines, ketopyrrolidines
Abstract: The structure-activity relationships of azetidine-based DPP IV inhibitors will be discussed in detail in the following review. The azetidine-based DPP IV inhibitors can be divided into three main subtypes, the 2-cyanoazetidines, 3-fluoroazetidines and 2-ketoazetidines. These subtypes have been explored and structure-activity relationships have been established by several groups. Several compounds within each of these subtypes display sub micromolar potency against DPP IV. The most potent cyanoazetidines and ketoazetidines have large, hydrophobic amino acid groups bound to the azetidine nitrogen and display activities below 100nM. DPP IV inhibition is not sensitive to stereochemistry at the 2- position as both 2-(R)- and 2-(S)-cyano and -keto azetidines display similar inhibitory potencies. While these “warhead”- based cyano- and ketoazetidines have the potential for covalent, bond-forming inhibition, they can also react to internally cyclize into inactive ketopiperazines and dihydroketopyrazine. Thus, chemical instability was also explored for compounds in these two subtypes and certain members of the cyanoazetidine series display aqueous stability comparable to the closely related cyanopyrrolidines. Select 3-fluoroazetidines also display inhibitory potencies below 1μM without the propensity for cyclization and chemical instability associated with the other subseries.
Export Options
About this article
Cite this article as:
Ferraris Dana, Belyakov Sergei, Li Weixing, Oliver Eddie, Ko Yao-Sen, Calvin David, Lautar Susan, Thomas Bert and Rojas Camilo, Azetidine-Based Inhibitors of Dipeptidyl Peptidase IV (DPP IV), Current Topics in Medicinal Chemistry 2007; 7 (6) . https://dx.doi.org/10.2174/156802607780090993
DOI https://dx.doi.org/10.2174/156802607780090993 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design
Drug development discovery has faced several challenges over the years. In fact, the evolution of classical approaches to modern methods using computational methods, or Computer-Aided Drug Design (CADD), has shown promising and essential results in any drug discovery campaign. Among these methods, molecular docking is one of the most notable ...read more
Drug Discovery in the Age of Artificial Intelligence
In the age of artificial intelligence (AI), we have witnessed a significant boom in AI techniques for drug discovery. AI techniques are increasingly integrated and accelerating the drug discovery process. These developments have not only attracted the attention of academia and industry but also raised important questions regarding the selection ...read more
From Biodiversity to Chemical Diversity: Focus of Flavonoids
Flavonoids are the largest group of polyphenols, plant secondary metabolites arising from the essential aromatic amino acid phenylalanine (or more rarely from tyrosine) via the phenylpropanoid pathway. The flavan nucleus is the basic 15-carbon skeleton of flavonoids (C6-C3-C6), which consists of two phenyl rings (A and B) and a heterocyclic ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Axonopathy Likely Initiates Neuropathological Processes Via a Mechanism of Axonal Leakage in Alzheimer's Mouse Models
Current Molecular Medicine Toxic Effects of Palladium Compounds on the Isolated Rat Heart
Medicinal Chemistry Neurotransmitters and Behavioral Alterations Induced by Nickel Exposure
Endocrine, Metabolic & Immune Disorders - Drug Targets Herbal Compounds and Toxins Modulating TRP Channels
Current Neuropharmacology Identification of Potent Caspase-3 Inhibitors for Treatment of Multi- Neurodegenerative Diseases Using Pharmacophore Modeling and Docking Approaches
CNS & Neurological Disorders - Drug Targets Applications of Cellular Systems Biology in Breast Cancer Patient Stratification and Diagnostics
Combinatorial Chemistry & High Throughput Screening MiR-335-5p Inhibits β-Amyloid (Aβ) Accumulation to Attenuate Cognitive Deficits Through Targeting c-jun-N-terminal Kinase 3 in Alzheimer’s Disease
Current Neurovascular Research Advances in Immunotherapy of Chronic Myeloid Leukemia CML
Current Cancer Drug Targets Promises and Challenges of Adult Stem Cells in Cancer Therapy
Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Discontinued) Roles of Arterial Baroreceptor Reflex During Bezold-Jarisch Reflex
Current Cardiology Reviews Network Medicine and High Throughput Screening
Current Drug Discovery Technologies WISP1 Neuroprotection Requires FoxO3a Post-Translational Modulation with Autoregulatory Control of SIRT1
Current Neurovascular Research Molecular Mechanisms of Biological Activity of Oleanolic Acid - A Source of Inspiration for A New Drugs Design
Mini-Reviews in Organic Chemistry Supportive-Expressive (SE) Psychotherapy: An Update
Current Psychiatry Reviews Phasic Dopamine Release in Appetitive Behaviors and Drug Addiction
Current Drug Abuse Reviews Formulation and Evaluation of Gastroretentive Microballoons Containing Baclofen for a Floating Oral Controlled Drug Delivery System
Current Drug Delivery Mucoadhesive Vaginal Drug Delivery Systems
Recent Patents on Drug Delivery & Formulation Patent Selections
Recent Patents on Drug Delivery & Formulation Effects of Chrysin on Serum Corticosterone Levels and Brain Oxidative Damages Induced by Immobilization in Rat
Cardiovascular & Hematological Disorders-Drug Targets Drug Delivery to CNS: Challenges and Opportunities with Emphasis on Biomaterials Based Drug Delivery Strategies
Current Pharmaceutical Design