Discovery of Clinical Candidate CHF-6366: A Novel Super-soft Dual Pharmacology Muscarinic Antagonist and β₂ Agonist (MABA) for the Inhaled Treatment of Respiratory Diseases

Abstract

The development of molecules embedding two distinct pharmacophores acting as muscarinic antagonists and β2 agonists (MABAs) promises to be an excellent opportunity to reduce formulation issues and boost efficacy through cross-talk and allosteric interactions. Herein, we report the results of our drug discovery campaign aimed at improving the therapeutic index of a previous MABA series by exploiting the super soft-drug concept. The incorporation of a metabolic liability, stable at the site of administration but undergoing rapid systemic metabolism, to generate poorly active and quickly eliminated fragments was pursued. Our SAR studies yielded MABA 29, which demonstrated a balanced in vivo profile up to 24 h, high instability in plasma and the liver, as well as sustained exposure in the lung. In vitro safety and non-GLP toxicity studies supported the nomination of 29 (CHF-6366) as a clinical candidate, attesting to the successful development of a novel super-soft MABA compound.

Designing drugs and chemical probes with the dualsteric approach

“…However, if the linker is too long, the high flexibility would also impair the potency and selectivity. 62,[233][234][235][236][237][238][239][240][241] In fact, a major workload in many researches is to decide the optimal length of the linker. To reduce the burden workflow, rational strategies are urgently needed.…”

“…In drug metabolism, however, dynamics linkers mean easier degradation of the linkers. As an example, Carzaniga et al 236 added an ester group into the alkyl linker of a dualsteric MR agonist. It was found that such a modification has a small effect on the overall potency but contributes greatly to metabolism.…”

“…Currently, some attempts have been made such as dynamic linkers. 169,236 More studies are required to improve its ADMET properties, for example, whether the dynamic linker approach could be promoted for more cases.…”

Discovery, Multiparametric Optimization, and Solid-State Driven Identification of CHF-6550, a Novel Soft Dual Pharmacology Muscarinic Antagonist and β2 Agonist (MABA) for the Inhaled Treatment of Respiratory Diseases

“…Nevertheless, they both appear to be discontinued and the examination of published preclinical and clinical data supports the speculation that the pharmacodynamic profile of the two pharmacological components (M 3 or β 2 ) could be divergent, with a predominance of one activity over the other, hampering the adjustment of doses when needed. 16 We were therefore encouraged to embark upon a drug discovery campaign aimed at developing an inhaled MABA that led first to the clinical candidate CHF-6366, whose discovery has been already described in a previous work, 15 and lately to the identification of a novel class of heterobifunctional diphenyl hydroxyacetic esters as inhaled MABA for respiratory diseases, the object of this work.…”

Unbinding Kinetics of Muscarinic M3 Receptor Antagonists Explained by Metadynamics Simulations

“…Considering our interest in SKRs on GPCR ligands, 29 and, in particular, in M3 antagonists as single 30,31 or dual targeting agents, 32,33 we selected the M3 receptor as a reference system, focusing our attention on a set of tiotropium analogues for which experimental RTs have been recently reported by Tautermann and colleagues (Figure 2), 34 and X-ray structures are currently available. Moderate modifications in the structure of tiotropium, including the removal of thiophene (1) or of an α-hydroxyl substituent (9), lead to a significant reduction in the experimental RT (over different orders of magnitude), suggesting that this set of compounds is suitable for the setup and test of computational protocols for SKR rationalization.…”