Abstract
The emergence of glucagon-like peptide 1 (GLP-1) as a well validated approach to the treatment of type 2 diabetes and preclinical validation of dipeptidyl peptidase IV (DPP-4) inhibition as an alternate, oral approach to GLP-1 therapy prompted the initiation of a DPP-4 inhibitor program at Merck in 1999. DPP-4 inhibitors threo- and allo-isoleucyl thiazolidide were in-licensed to jump start the program; however, development was discontinued due to profound toxicity in rat and dog safety studies. The observation that both compounds inhibit the related proline peptidases DPP8 and DPP9 led to the hypothesis that inhibition of DPP8 and/or DPP9 could evoke severe toxicities in preclinical species. Indeed, the observed toxicities were recapitulated with a selective dual DPP8/9 inhibitor but not with an inhibitor selective for DPP-4. Thus, medicinal chemistry efforts focused on identifying a highly selective DPP-4 inibitor for clinical development. Initial work in an α-amino acid series related to isoleucyl thiazolidide was discontinued due to lack of selectivity; however, SAR studies on two screening leads led to the identification of a highly selective β-amino acid piperazine series. In an effort to stabilize the piperazine moiety, which was extensively metabolized in vivo, a series of bicyclic derivatives were prepared, culminating in the identification of a potent and selective triazolopiperazine series. Unlike their monocyclic counterparts, these analogs typically showed excellent pharmacokinetic properties in preclinical species. Optimization of this series led to the discovery of JANUVIA™ (sitagliptin), a highly selective DPP-4 inhibitor for the treatment of type 2 diabetes.
Keywords: DPP-4-deficient mice, peptide scanning libraries, melanocortin 4 receptor (MC4-R), DPP-4 inhibitor, hypoglycemia
Current Topics in Medicinal Chemistry
Title: Discovery of JANUVIA TM (Sitagliptin), a Selective Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type2 Diabetes.
Volume: 7 Issue: 6
Author(s): Nancy A. Thornberry and Ann E. Weber
Affiliation:
Keywords: DPP-4-deficient mice, peptide scanning libraries, melanocortin 4 receptor (MC4-R), DPP-4 inhibitor, hypoglycemia
Abstract: The emergence of glucagon-like peptide 1 (GLP-1) as a well validated approach to the treatment of type 2 diabetes and preclinical validation of dipeptidyl peptidase IV (DPP-4) inhibition as an alternate, oral approach to GLP-1 therapy prompted the initiation of a DPP-4 inhibitor program at Merck in 1999. DPP-4 inhibitors threo- and allo-isoleucyl thiazolidide were in-licensed to jump start the program; however, development was discontinued due to profound toxicity in rat and dog safety studies. The observation that both compounds inhibit the related proline peptidases DPP8 and DPP9 led to the hypothesis that inhibition of DPP8 and/or DPP9 could evoke severe toxicities in preclinical species. Indeed, the observed toxicities were recapitulated with a selective dual DPP8/9 inhibitor but not with an inhibitor selective for DPP-4. Thus, medicinal chemistry efforts focused on identifying a highly selective DPP-4 inibitor for clinical development. Initial work in an α-amino acid series related to isoleucyl thiazolidide was discontinued due to lack of selectivity; however, SAR studies on two screening leads led to the identification of a highly selective β-amino acid piperazine series. In an effort to stabilize the piperazine moiety, which was extensively metabolized in vivo, a series of bicyclic derivatives were prepared, culminating in the identification of a potent and selective triazolopiperazine series. Unlike their monocyclic counterparts, these analogs typically showed excellent pharmacokinetic properties in preclinical species. Optimization of this series led to the discovery of JANUVIA™ (sitagliptin), a highly selective DPP-4 inhibitor for the treatment of type 2 diabetes.
Export Options
About this article
Cite this article as:
Thornberry A. Nancy and Weber E. Ann, Discovery of JANUVIA TM (Sitagliptin), a Selective Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type2 Diabetes., Current Topics in Medicinal Chemistry 2007; 7 (6) . https://dx.doi.org/10.2174/156802607780091028
DOI https://dx.doi.org/10.2174/156802607780091028 |
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
-
Renin Angiotensin System (RAS) and Immune System Profile in Specific Subgroups with COVID-19
Current Medicinal Chemistry Guanylate Cyclase C: A Current Hot Target, from Physiology to Pathology
Current Medicinal Chemistry The Long Term Biological Consequences of Anorexia Nervosa
Current Nutrition & Food Science Substance Abuse, HIV-1 and Hepatitis
Current HIV Research Non-Communicable Diseases and Adherence to Mediterranean Diet
Endocrine, Metabolic & Immune Disorders - Drug Targets Potential Anticancer Properties of Bisphosphonates: Insights From Preclinical Studies
Anti-Cancer Agents in Medicinal Chemistry Pathology and Development - Developmental Systems for Target Validation and Drug Screening in Osteoarthritis
Drug Design Reviews - Online (Discontinued) Tumor-Targeting Peptides and Small Molecules as Anti-Cancer Agents to Overcome Drug Resistance
Current Medicinal Chemistry Novel Antimicrobial Agents for the Management of Maxillofacial and Neck Infections
Recent Patents on Anti-Infective Drug Discovery Cyclopropyl Scaffold: A Generalist for Marketed Drugs
Mini-Reviews in Medicinal Chemistry Preclinical Evaluation of New Taxoids
Current Pharmaceutical Design Nerve Growth Factor in Alcohol Use Disorders
Current Neuropharmacology subject Index To Volume 2
Current Protein & Peptide Science Multifunctional Role of Pacap-Like Peptides in Molluscs
Protein & Peptide Letters The Use of the Zebrafish Model to Aid in Drug Discovery and Target Validation
Current Topics in Medicinal Chemistry Neuroinflammation: A Therapeutic Target of Cotinine for the Treatment of Psychiatric Disorders?
Current Pharmaceutical Design Fgf10: A Paracrine-Signaling Molecule in Development, Disease, and Regenerative Medicine
Current Molecular Medicine Cellular Actions of Nesfatin-1 on Hypothalamic and Medullary Neurons
Current Pharmaceutical Design Potential Therapeutic Targets for Neurodegenerative Diseases: Lessons Learned from Calorie Restriction
Current Drug Targets Pleiotropic Effects of Cathepsin D
Endocrine, Metabolic & Immune Disorders - Drug Targets