Design and characterization of a surfactant‐conjugated, long‐acting, balanced <scp>GLP</scp>‐1/glucagon receptor dual agonist
John J. Nestor, Xiaoming Zhang, Sarah Jaw‐Tsai, David G. Parkes, Cyrus K. Becker
Abstract
Abstract Existing candidates for treating non‐alcoholic steatohepatitis (NASH), including glucagon‐like peptide‐1 (GLP‐1) analogs and previous GLP‐1/glucagon receptor (GLP‐1R/GCGR) dual agonists, do not address the need for substantial weight loss adequately. We sought a more effective, evenly balanced GLP‐1/GCGR dual agonist suitable for weekly administration. We studied a new class of covalent modifiers, glycolipid surfactants, to prolong the duration of action of candidate peptides. Variation of the hydrophobic tail of such surfactant modifications resulted in a wide and tunable range of physical properties and t 1/2 values. We selected compound 17 , which demonstrated high, evenly balanced potency for activation of human GLP‐1R and GCGRs, return of diet induced obese (DIO) rodents to lean body/liver weight and prolonged duration correlated with high serum albumin binding. We observed a prolonged pharmacodynamic (PD) profile in rodents and pharmacokinetics (PK) in mini‐pigs ( t 1/2 = 52 hours, mean residence time, MRT = 86 hours), suggesting suitability for weekly dosing. Accordingly, 17 (ALT‐801) was selected for clinical development.