Obesity is one of the major risk factors for
type 2 diabetes, and the development of agents, that can simultaneously achieve
glucose control and
weight loss, is being actively pursued.
Therapies based on
peptide mimetics of the gut
hormone glucagon-like peptide 1 (GLP-1) are rapidly gaining favor, due to their ability to increase insulin secretion in a strictly
glucose-dependent manner, with little or no risk of
hypoglycemia, and to their additional benefit of causing a modest, but durable
weight loss.
Oxyntomodulin (OXM), a 37-amino
acid peptide hormone of the
glucagon (GCG) family with dual agonistic activity on both the
GLP-1 (GLP1R) and the GCG (GCGR) receptors, has been shown to reduce food intake and
body weight in humans, with a lower incidence of treatment-associated
nausea than
GLP-1 mimetics. As for other
peptide hormones, its clinical application is limited by the short circulatory half-life, a major component of which is cleavage by the
enzyme dipeptidyl peptidase IV (DPP-IV). SAR studies on OXM, described herein, led to the identification of molecules resistant to DPP-IV degradation, with increased potency as compared to the natural
hormone. Analogs derivatized with a
cholesterol moiety display increased duration of action in vivo. Moreover, we identified a single substitution which can change the OXM pharmacological profile from a dual GLP1R/GCGR agonist to a selective GLP1R agonist. The latter finding enabled studies, described in detail in a separate study (Pocai A, Carrington PE, Adams JR, Wright M, Eiermann G, Zhu L, Du X, Petrov A, Lassman ME, Jiang G, Liu F, Miller C,
Tota LM, Zhou G, Zhang X, Sountis MM, Santoprete A, Capitò E, Chicchi GG, Thornberry N, Bianchi E, Pessi A, Marsh DJ, SinhaRoy R.
Glucagon-like peptide 1/
glucagon receptor dual agonism reverses
obesity in mice. Diabetes 2009; 58: 2258-2266), which highlight the potential of GLP1R/GCGR dual agonists as a potentially superior class of
therapeutics over the pure GLP1R agonists currently in clinical use.