George W. Holland

Discovery, structure-activity relationships, pharmacokinetics, and efficacy of glucokinase activator (2R)-3-cyclopentyl-2-(4-methanesulfonylphenyl)-N-thiazol-2-yl-propionamide (RO0281675).

Glucokinase (GK) is a glucose sensor that couples glucose metabolism to insulin release. The important role of GK in maintaining glucose homeostasis is illustrated in patients with GK mutations. In this publication, identification of the hit molecule 1 and its SAR development, which led to the discovery of potent allosteric GK activators 9a and 21a, is described. Compound 21a (RO0281675) was used to validate the clinical relevance of targeting GK to treat type 2 diabetes.

Benzenepropanoic acids containing chromanone or naphthalenone moieties are potent and orally active leukotriene B4 antagonists

Abstract Systematic structural modification of peptidoleukotriene antagonists of the o-hydroxyacetophenone class has led to the discovery of certain [[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]alkyl]benzenepropanoic acids and related compounds ( 7 ), which appear to be potent and selective antagonists of the proinflammatory mediator leukotriene B 4 .

Chapter 7. Pulmonary and Antiallergy Agents

Publisher Summary This chapter discusses the researches made during the past year on pulmonary and antiallergy agents. Clinical tests have proved that several leukotriene D 4 (LTD 4 ), the “first generation” compounds are not potent enough to fully test their role in treating asthmatics. More potent, orally-active compounds have recently been reported. LTB 4 is hypothesized to be a potential mediator of lung eosinophilia in asthmatics. For this reason, LTB 4 antagonists may be useful in treating asthma. Of special interest with regard to future antiasthmatic therapy are reports of new, orally-active, selective 5-LO inhibitors. ICI 207, 968 has been reported to be 200-times more potent an inhibitor of 5-LO than CO. The thromboxane (TXA 2 ) antagonist, GR 32191, has been reported to decrease allergen-induced bronchoconstriction in man. Phospholipases in the signal transduction mechanisms found in key cells are associated with the initiation of asthmatic disease. Two β 2 -adrenoceptor agonists, salmeterol, and formoterol have been evaluated clinically by inhalation. Recent progress in the cloning of the subunits of the human IgE receptor may allow the future development of high flux in vitro screens for non-peptide antagonists. In addition, histamine release inhibitory factors have been identified and may be novel tools in the development of mediator release inhibitors (MRI). Vasoactive intestinal peptide (VIP) has been postulated to be the peptide mediator of the non-adrenergic, non-cholinergic, inhibitory pathway. Thus, VIP may be an important endogenous bronchodilator in man. Pirenzepine, an orally-active specific M1 antagonist, increased lung volume in both large and small airways in asthmatics. These results indicated the functional role of M1 receptors in human airways and suggest the potential for the development of anticholinergic drugs based on pirenzepine.