Discovery of a novel class of inhaled dual pharmacology muscarinic antagonist and β2 agonist (MABA) for the treatment of chronic obstructive pulmonary disease (COPD)

Designing drugs and chemical probes with the dualsteric approach

“…In more cases, dualsteric modulators are designed by combining the orthosteric and allosteric ligand with a linker. 50,56,57,59,62,63,65,66,69,70,73,75,77–86,88,89,91,92,96,97,99,100,102–104,106–109,111,114–118,120–123,126,127,132,133,136,138,140,143,145,148–150,153,154,156,160,161,163,165,166,169,170,178–182,185,186,188,195,228 This is similar with the fragment-based drug discovery (FBDD). 229 The core fragments of drug binding is first identified and then the fragments are grown, merged, or linked into one complete molecule.…”

“…After a manual filtering, 133 research articles focusing on identifications of novel dualsteric modulators were found. Modulators targeting GPCR 50,53,56–137 or kinase 138–157 account for more than three quarters (Fig. 5).…”

“…GPCR itself has accommodated 62.4% targets of reports. 50,53,56–137 GPCR is a class of 7-transmembrane (7TM) proteins decorated on the cell membrane for transduction amplification of exterior signals into cells. 189 They are vital in many physiological processes and are therefore popular drug targets for a series of diseases like cancers and neurological disorders.…”

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

“…In addition, relying on MABA compounds’ physical properties and wishing to exploit a route of administration potentially leading to minimization of systemic exposure, the inhaled route was deemed the most suitable method for this class of molecules. Furthermore, while undertaking our drug discovery campaign we settled on adding a further challenge to the already complex design of multivalent molecules by applying a super soft-drug approach, and aiming at improving the therapeutic index of our previous lead, we installed an ester in the linker portion of our compounds. Our SAR studies revealed that such a moiety was not only tolerated in terms of potency but also able to deliver molecules with fast enzymatic hydrolysis both in the liver and in plasma.…”

“…Thus, our MABA drug discovery program presented significant challenges: (1) design of dual pharmacology compounds which display comparable efficacy and duration of action at each of the individual targets; (2) improvement of the therapeutic index (TI) of our previous series through the introduction of a metabolic liability; (3) development of molecules suitable for delivery by inhalation (lung persistency and low probability of accumulation).…”