Atropisomer Control in Macrocyclic Factor VIIa Inhibitors

Abstract

Incorporation of a methyl group onto a macrocyclic FVIIa inhibitor improves potency 10-fold but is accompanied by atropisomerism due to restricted bond rotation in the macrocyclic structure, as demonstrated by NMR studies. We designed a conformational constraint favoring the desired atropisomer in which this methyl group interacts with the S2 pocket of FVIIa. A macrocyclic inhibitor incorporating this constraint was prepared and demonstrated by NMR to reside predominantly in the desired conformation. This modification improved potency 180-fold relative to the unsubstituted, racemic macrocycle and improved selectivity. An X-ray crystal structure of a closely related analogue in the FVIIa active site was obtained and matches the NMR and modeled conformations, confirming that this conformational constraint does indeed direct the methyl group into the S2 pocket as designed. The resulting rationally designed, conformationally stable template enables further optimization of these macrocyclic inhibitors.

Neutral Unsymmetrical Coordinated Cyclophane Polymerization Catalysts

“…An additional 3,5‐dimethyl substitution pattern was employed on these rings, as this has been found to provide a sensitive probe for their impact on catalysis [13] . Despite the stronger steric hindrance in the 2‐position, the higher transmetalation reactivity of the iodide enabled selective copper‐assisted cross‐coupling [14] of 5‐bromo‐1,3‐dimethyl‐2‐iodobenzene with allyl bromide to give 1 , with an intact aryl‐bromide (cf. the Supporting Information, for experimental details and characterization data of all compounds).…”

Design and Synthesis of Novel Meta-Linked Phenylglycine Macrocyclic FVIIa Inhibitors

“…Both enantiomers of the macrocycle containing the benzylic methyl group were prepared (Table 4), and it was discovered that the (R)-enantiomer (26, assigned by X-ray cocrystal structure, Figure 5) was significantly more potent than the (S)-enantiomer (25), resulting in a 100-fold increase in TF/FVIIa potency over the unsubstituted compound (21) (see Figure 5), with concomitant improvement in the FVIIa deficient prothrombin time assay. Selected compounds from this series were studied in rat oral PK once promising potency, permeability, and metabolic stability was achieved.…”

Synthesis and P1′ SAR exploration of potent macrocyclic tissue factor-factor VIIa inhibitors

“…Building on the initial success of the macrocyclization strategy applied to FVIIa inhibitors, Glunz et al further enhanced this approach by utilizing rational structure-guided atropisomer control via incorporation of a P2 benzylic methyl group, and thereby locking macrocyclic scaffold in the bioactive conformation. 14 From the resulting conformationally stable macrocyclic template, Zhang et al subsequently undertook detailed structure-activity relationship (SAR) studies in the P1 and P1′ regions of the macrocyclic core. 15 After surveying a number of P1′ moieties, cyclopropyl sulfone was identified as an optimal group.…”

“…Macrocycles 10 (Figure 2) and 46 (Table 1) were accessed starting from the precursor 18 utilizing a general synthetic sequence we have disclosed earlier. 14,15 Additional macrocyclic structures 52-55 were constructed as outlined in Scheme 4 from previously described phenylglycine 47. 15 BOP coupling of the respective precursors afforded the required aminophenyl alcohols 48-52 in good yields.…”

“…15 BOP coupling of the respective precursors afforded the required aminophenyl alcohols 48-52 in good yields. Our previously reported two-step carbamoylation protocol 14 involving phosgene functionalization and subsequent slow addition to a dilute MeCN solution of an amine base afforded the corresponding macrocyclic carbamates, which after saponification and Boc removal yielded the desired macrocycles 53-57. 24 To further probe charged interactions with Lys60A, an acid surrogate was introduced at the P1′ moiety.…”