The Discovery of the Dipeptidyl Peptidase-4 (DPP4) Inhibitor Onglyza: From Concept to Market - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 1

CHAPTER 1
The Discovery of the Dipeptidyl
Peptidase-4 (DPP4) Inhibitor
Onglyza t : From Concept to
Market
JEFFREY A. ROBL AND LAWRENCE G. HAMANN
Bristol-Myers Squibb Research & Development, Department of Discovery
Chemistry - Metabolic Diseases, P.O. Box 5400, Princeton, NJ 08543, USA
1.1 Introduction
The prevalence of diabetes in developed and now emerging countries represents
a significant health burden to a large portion of the world's population. Type-2
diabetic patients, characterized in part by elevated fasting plasma glucose of
4125mg dL 1 (7.0mmol L 1 ) and glycosylated hemoglobin (HbA1c) Z6%,
are at increased risk for the development of both microvascular (retinopathy,
neuropathy, nephropathy) as well as macrovascular complications (myocardial
infarction, stroke). As such, diabetes is the leading cause of blindness, kidney
failure, and limb amputation worldwide. 1 Diabetes is a progressive disease,
with morbidity and mortality risk increasing with both duration and severity of
hyperglycemia. Additionally, diabetes is also now impacting different popula-
tion sectors (adolescents, developing countries) not typically associated with
the disease 30 years ago. Consequently, the continually increasing diabetes
prevalence is placing greater strain on both health care systems and economies
on a global scale. In 2007 alone, studies have shown that diabetes cost the US