8 Experimental Diabetes Research
complex and likely diﬃcult to mimic with low molecular
weight compounds, examples of small molecules working
via an allosteric mode provide compelling evidence that
medicinal chemistry strategies for this target should be
considered. Further, the application of advanced structural
biology methodologies and more sophisticated assay systems
and testing schemes, including work to understand biased
signaling for GLP-1 receptor ligands, will likely be needed to
advance drug-like molecules.
While this paper was under editorial review, a patent ap-
plication from Receptos Inc. (WO2011/156655 A2) was pub-
lished disclosing novel compounds with allosteric modulator
activity at the GLP-1 receptor.
F. S. Willard, A. B. Bueno, and K. W. Sloop contributed
equally to this paper.
Conﬂict of Interests
All authors are employees of Eli Lilly and Company and may
own company stock or possess stock options.
 J. J. Holst, “Glucagon-like peptide-1: from extract to agent.
The claude bernard lecture, 2005,” Diabetologia, vol. 49, no.
2, pp. 253–260, 2006.
 J. A. Lovshin and D. J. Drucker, “Incretin-based therapies for
type 2 diabetes mellitus,” Nature Revie ws Endocrinology, vol. 5,
no. 5, pp. 262–269, 2009.
J. A. Williams, “Drugability of extra cellular targets: discover y
of small molecule drugs targeting allosteric, functional, and
subunit-selective sites on GPCRs and ion channels,” Neuropsy-
chopharmacology, vol. 34, no. 1, pp. 106–125, 2009.
 S. R. Hoare, “Mechanisms of peptide and nonpeptide ligand
binding to Class B G-protein-coupled receptors,” Drug Discov-
ery Today, vol. 10, no. 6, pp. 417–427, 2005.
angstrom crystal structure of a human A2A adenosine recep-
tor bound to an antagonist,” Science, vol. 322, no. 5905, pp.
 T. Warne, M. J. Serrano-Vega, J. G. Baker et al., “Structure of a
β1-adrenergic G-protein-coupled receptor,” Nature, vol. 454,
no. 7203, pp. 486–491, 2008.
 T. Warne, R. Moukhametzianov, J. G. Baker et al., “The struc-
tural basis for agonist and partial agonist action on a beta(1)-
adrenergic receptor,” Nature, vol. 469, no. 7329, pp. 241–244,
 V. Cherezov, D. M. Rosenbaum, M. A. Hanson et al., “High-
resolution crystal structure of an engineered human β2-
adrenergic G protein-coupled receptor,” Science, vol. 318, no.
5854, pp. 1258–1265, 2007.
 E. Y. Chien, W. Liu, Q. Zhao et al., “Structure of the human
dopamine D3 receptor in complex w ith a D2/D3 selective
antagonist,” Science, vol. 330, no. 6007, pp. 1091–1095, 2010.
 T. Shimamura, M. Shiroishi, S. Weyand et al., “Structure of
the human histamine H 1 receptor complex with doxepin,”
Nature, vol. 475, no. 7354, pp. 65–72, 2011.
 C. Koole, D. Wootten, J. Simms et al., “Allosteric ligands of
the glucagon-like peptide 1 receptor (GLP-1R) diﬀerentially
modulate endogenous and exogenous peptide responses in a
pathway-selective manner: implications for drug screening,”
Molecular Pharmacology, vol. 78, no. 3, pp. 456–465, 2010.
 L. B. Knudsen, D. Kiel, M. Teng et al., “Small-molecule ago-
nists for the glucagon-like peptide 1 receptor,” Proceedings of
the National Academy of Sciences of the United States of Amer-
ica, vol. 104, no. 3, pp. 937–942, 2007.
 K. W. Sloop, F. S. Willard, M. B. Brenner et al., “Novel small
molecule glucagon-like peptide-1 receptor agonist stimulates
insulin secretion in rodents and from human islets,” Diabetes,
vol. 59, no. 12, pp. 3099–3107, 2010.
 W. P. Walters and M. A. Murcko, “Prediction of “drug-like-
ness,” Advanced Dr ug Delivery Reviews, vol. 54, no. 3, pp. 255–
 C. A. Lipinski, “Dr ug-like properties and the causes of poor
solubility and poor permeability,” Journal of Pharmacological
and Toxicological Methods, vol. 44, no. 1, pp. 235–249, 2000.
Ward, and K. D. Kopple, “Molecular properties that inﬂu-
ence the oral bioavailability of drug candidates,” Journal of
Medicinal Chemistry, vol. 45, no. 12, pp. 2615–2623, 2002.
 A. Gronberg, E.-R. Sol, A. Danielsson et al., “A low molecular
weight non-peptide antagonist of glucagon-like peptide-1,”
Diabetes, vol. 49, supplement 1, p. A251, 2000.
 E. C. Tibaduiza, C. Chen, and M. Beinborn, “A small mole-
cule ligand of the glucagon-like peptide 1 receptor targets
its amino-terminal hormone binding domain,” Journal of
Biological Chemistry, vol. 276, no. 41, pp. 37787–37793, 2001.
 S. Runge, H. Thøgersen, K. Madsen, J. Lau, and R. Rudolph,
“Crystal structure of the ligand-bound glucagon-like peptide-
1 receptor extracellular domain,” Journal of Biological Chem-
istry, vol. 283, no. 17, pp. 11340–11347, 2008.
 C. R. Underwood, P. Garibay, L. B. Knudsen et al., “Crystal
structure of glucagon-like peptide-1 in complex with the
extracellular domain of the glucagon-like peptide-1 receptor,”
Journal of Biological Chemistry, vol. 285, no. 1, pp. 723–730,
 A. S. Kopin and M. Beingorn, WO2004/203310 Methods and
Compositions for the Treatment of Metabolic Disorders, 2004.
 L. K. Truesdale et al., “US 6,469,021 B1 Non-Peptide Antago-
nists Of GLP-1 Receptor And Methods Of Use,” U.S. Patent,
Editor, Agouron Pharmaceuticals, San Diego, Calif, USA,
 D. R. Gehlert, A. Cippitelli, A. Thorsell et al., “3-(4-Chloro-
dimethyl-imidazo[1,2-b]pyridazine: a novel brain-penetrant,
orally available corticotropin-releasing factor receptor 1
antagonist with eﬃcacy in animal models of alcoholism,”
Journal of Neuroscience, vol. 27, no. 10, pp. 2718–2726, 2007.
 J. Lau, G. Behrens, U. G. Sidelmann et al., “New β-alanine
derivatives are orally available glucagon receptor antagonists,”
Journal of Medicinal Chemistry, vol. 50, no. 1, pp. 113–128,
 J. L. Duﬀy, B. A. Kirk, Z. Konteatis et al., “Discovery and
investigation of a novel class of thiophene-derived antagonists
of the human glucagon receptor,” Bioorganic and Medicinal
Chemistry Letters, vol. 15, no. 5, pp. 1401–1405, 2005.
 D. M. Shen, F. Zhang, E. J. Brady et al., “Discover y of novel,
potent, and orally active spiro-urea human glucagon receptor