Discovery of BGM1812, a Novel Dual Amylin and Calcitonin Receptor Agonist for Obesity Treatment

Parallel activation of the calcitonin receptor (CTR)
and amylin
receptor (AMYR) is considered a more effective weight-loss strategy.
Although the novel dual amylin and calcitonin receptor agonist (DACRA),
petrelintide, is currently undergoing phase II clinical trials, its
agonistic activity remains insufficient compared with natural agonists.
Further optimization of the agonistic capabilities of petrelintide
is an attractive strategy for developing DACRAs. Due to the lack of
structure–activity relationship (SAR) and target binding information,
a step-by-step process involving three rounds of modifications was
performed guided by structure-based drug design and molecular dynamics
(MD) simulations. Two successful methylation strategies led to the
identification of the more efficient novel DACRA, BGM1812, with excellent
performance in terms of half-life, stability, and solubility. In both
in vivo and in vitro studies, BGM1812 showed significantly enhanced
efficacy. This finding provides valuable insights into the SAR of
petrelintide and highlights the potential of BGM1812 as a promising
obesity drug candidate.