Bernard Hulin

New hypoglycaemic agents.

Publisher Summary This chapter focuses on new hypoglycaemic agents. Diabetes mellitus is a disease characterized by excess glucose in the plasma and by various other metabolic abnormalities, including dyslipidaemia. In the United States 6-12 million people are believed to be affected, among which the majority suffer from non-insulin dependent diabetes mellitus (NIDDM or type II) and the rest (500,000) from insulin dependent diabetes mellitus (IDDM or type I). The development of NIDDM has been linked to both genetic factors (the prevalence of NIDDM varies widely among racial groups) and environmental factors, such as diet, obesity and lack of physical exercise. A body of evidence is accumulating to suggest that tight blood glucose control is important in order to prevent or delay the onset of these complications and a large scale clinical study, the Diabetes Control and Complications Trial (DCCT), has been undertaken in order to provide a definitive answer to this question. The goals of new therapeutic approaches for both IDDM and NIDDM have been and continue to be the provision of tight control both in the fasting and postprandial state and the correction of other metabolic abnormalities. Insulin is the primary therapy for all IDDM patients and is prescribed to NIDDM patients who do not respond to sulphonylureas or biguanides. Porcine insulin is slowly being replaced by human insulin, the majority of which is produced by recombinant DNA technology. The chapter also describes agents that either modulate or mimic insulins actions in muscle, its main target tissue for glucose disposal.

(3,3-Difluoro-pyrrolidin-1-yl)-[(2S,4S)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone: A potent, selective, orally active dipeptidyl peptidase IV inhibitor

A series of 4-substituted proline amides was synthesized and evaluated as inhibitors of dipeptidyl pepdidase IV for the treatment of type 2 diabetes. (3,3-Difluoro-pyrrolidin-1-yl)-[(2S,4S)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone (5) emerged as a potent (IC(50) = 13 nM) and selective compound, with high oral bioavailability in preclinical species and low plasma protein binding. Compound 5, PF-00734200, was selected for development as a potential new treatment for type 2 diabetes.

Synthesis of a biotin conjugate of darglitazone, a new antidiabetic agent. A general protocol for the reversible biotinylation of ketones

Abstract Biotin conjugates of darglitazone (CP-86,325), a new antihyperglycemic agent, were prepared. The protocol used allows variation of the chain linking the two units and is applicable to other ligands containing a ketone function.