Discovery of M₃ Antagonist-PDE4 Inhibitor Dual Pharmacology Molecules for the Treatment of Chronic Obstructive Pulmonary Disease

Abstract

In this paper, we report the discovery of dual M3 antagonist-PDE4 inhibitor (MAPI) compounds for the inhaled treatment of pulmonary diseases. The identification of dual compounds was enabled by the intuition that the fusion of a PDE4 scaffold derived from our CHF-6001 series with a muscarinic scaffold through a common linking ring could generate compounds active versus both the transmembrane M3 receptor and the intracellular PDE4 enzyme. Two chemical series characterized by two different muscarinic scaffolds were investigated. SAR optimization was aimed at obtaining M3 nanomolar affinity coupled with nanomolar PDE4 inhibition, which translated into anti-bronchospastic efficacy ex vivo (inhibition of rat trachea contraction) and into anti-inflammatory efficacy in vitro (inhibition of TNFα release). Among the best compounds, compound 92a achieved the goal of demonstrating in vivo efficacy and duration of action in both the bronchoconstriction and inflammation assays in rat after intratracheal administration.

Optimization of M3 Antagonist–PDE4 Inhibitor (MAPI) Dual Pharmacology Molecules for the Treatment of COPD

“…The cyclopropylmethoxy substitution on the phenyl linking ring was coupled with the α-hydroxymethyl group in the muscarinic portion of compounds 3f/s, and the α-hydroxymethyl group and the two single diastereomers 9f and 9s were synthesized and tested (Table 5), with both showing a good PDE4 activity. The R-hydroxymethyl stereoisomer of compound 9 was docked in the 8OEG PDE4B catalytic site and confirmed the same binding mode of the cocrystallized inhibitor 92a (having an R configuration in the phenylglycine portion), 6 with the cyclopropylmethoxy moiety that fills the hydrophobic subpocket described above (Figure 3). The cyclopropylmethoxy substituent is able to improve PDE4B2 potency finding additional good hydrophobic contacts, in particular with Phe 586, Met 603, and Pro 602.…”

“…At this stage, our attention turned to the catechol region of the PDE4 fragment; we hypothesized that modification of the ether substituents could impact the balance between the two pharmacological targets, based on our previous findings that lipophilicity of the substituents in this area impacted the activity in the functional assay. 6 The replacement of the methoxy group at the 3-position in 3s with the slightly more lipophilic ethoxy group and with the rather more lipophilic and historical cyclopropylmethoxy group 7,8 was investigated. Compounds 10f, 10s, 11f, and 11s appeared to retain activity at both pharmacological targets (Table 6).…”

“…Intermediates 14, 36, 37, and 38 have been previously described as compounds 11, 85a, 48, and 84a, respectively. 6 Also, intermediate 41c has been previously described as compound 25s. 8 Final Compounds 2, 1, and 5.…”

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.…”

Tropylium Salt-Promoted Vinylogous Aza-Michael Addition of Carbamates to para-Quinone Methides: Elaboration to Diastereomerically Pure α,α′-Diarylmethyl Carbamates

“…These compounds have been well-recognized in the area of medicinal chemistry, and many α,α′-diarylmethyl amine-based drugs have been already commercialized (Figure 1). 21,22 Numerous synthetic methods have been established to access α,α′-diarylmethyl amine or carbamate derivatives, 23 including the arylation of imines, 24−29 the amination of diarylmethanols, 30−37 benzylic C−H amination via crossdehydrogenative coupling, 38,39 the Lossen rearrangement of hydroxamic acids, 40,41 the reduction and transfer hydrogenation of imines, 42−50 the direct reductive amination of ketones, 51−55 QMs through the base-or Lewis acid-mediated or catalyzed vinylogous conjugate addition of amines and amides. 58−61 Recently, our research group has explored the inimitable reactivity of p-QMs to access unsymmetrical diaryl-and triarylmethane derivatives, carbocycles, and heterocycles.…”