Pergamon Bioorganic & Medicinal Chemistry Letters 9 (1999) 641-646 BIOORGANIC & MEDICINAL CHEMISTRY LETTERS POTENT, ORALLY ABSORBED GLUCAGON RECEPTOR ANTAGONISTS Stephen E. de Laszlo,* Candice Hacker, Bing Li, Dooseop Kim, Malcolm MacCoss, Nathan Mantlo, James V. Pivnichny, Larry Colwell, Gregory E. Koch, a Margaret A. Cascieri a and William K. Hagmann Departments of Medicinal Chemistry and aMolecular Pharmacology & Biochemistry, Merck Research Laboratories, PO Box 2000 Rahway, N.J. 07065, U.S.A. Received 12 October 1998; accepted 24 December 1998 Abstract: The SAR of 2-pyridyl-3,5-diaryl pyrroles, ligands of the human glucagon receptor and inhibitors of p38 kinase, were investigated. This effort resulted in the identification of 2-(4-pyridyl)-5-(4-chlorophenyl)-3-(5- bromo-2-propyloxyphenyl)pyrrole 49 (L-168,049), a potent (Kb = 25 riM), selective antagonist of glucagon. © Elsevier Science Ltd. All rights reserved. Introduction Glucagon is a major counterregulatory hormone to insulin, stimulatingglycogenolysis and gluconeogenesis. 1 Glucagon is a 29 amino acid peptide produced in the t~-cells of the pancreas from a prec peptide preproglucagon which is processed in the pancreas to give glucagon and, in the intestine, to provide glucagon like peptide 1 (GLP-1). 2 The receptors for glucagon are found primarily in the liver. The glucagon receptor is a 7 membrane spanning G-protein linkedprotein. Occupation of the receptor on hepatocytes by glucagon stimulates adenyl cyclase and increases free Ca 2÷, resulting in increased glucose output) Hyperglucagonemia occurs in both insulin dependant diabetes (Type I) and non-insulin dependent dia (Type II). In both disease states the glucagon/insulin and glucagon/glucose ratios are elevated. The bihormonal hypothesis proposes that both insulin and glucagon contribute to elevated levels of glucose in diabetics. 4 Therefore, a glucagon receptor antagonist may mediate the formation of hepatic glucose, lower fasting glucose levels and improve glucose tolerance in diabetics. Considerable progress directed at identifying a peptide antagonist of glucagon has been reportedJ A nonpeptide antagonist would have pharmacokinetic advantages over a peptidyl drug. CP-99,711 was rep displace ~25I-glucagon from rat liver receptors at low micromolar concentrations and to antagonise glucagon stimulated cyclic adenosine monophosphate (cAMP) production in rat liver homogenates. 6 More recently substituted pyridines and biphenyls have been claimed as glucagon antagonists] We wish to report the disc of a series of ligands of the human and murine glucagon receptor. 8 Of these ligands, two, 11 and 49, h demonstrated to be orally bioavailable antagonists of the human glucagon receptor. Chemistry Compounds were prepared by adaptation of methods 1-3 which are illustrated in Scheme 1. 9 Condensation of the silyl acyloin A with an acetophenone B provided low yields of the pyrroles C in a o reaction.m A higher yielding route was developed from the 4-fluorophenyl acetopyridine D, prepared by alkylation of 4-pyridine carboxaidehyde dimethylacetal with 4-fluorobenzyl bromide followed by acid catalyzed hydrolysis." Alkylation of D with ct-bromo ketones, j2 followed by condensation with ammonia formed in situ by heating ammonium carbonate in acetic acid formed pyrroles F in excellent yield. Analogs with 3-position variations were predominantly prepared via method 3. Chalcones G are commercially available or readily prepared by condensation of 4'-chloro acetophenone F with an aldehyde. Application of the Stetter reaction provided the 1,4-diketone H in good yield, which in turn were converted to the desired pyrroles IJ 3 The synthetic method and chemical conversions amongst analogs are indicated below the Tables 1-3. 0960-894X/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved. PH: S0960-894X(99)00081-5