UDP and UDP-glucose
activate the P2Y14 receptor (P2Y14R) to modulate
processes related to inflammation, diabetes,
and asthma. A computational pipeline suggested alternatives to naphthalene
of a previously reported P2Y14R antagonist (3, PPTN) using docking and molecular dynamics simulations on a hP2Y14R homology model based on P2Y12R structures. By
reevaluating the binding of 3 to P2Y14R computationally,
two alternatives, i.e., alkynyl and triazolyl derivatives, were identified.
Improved synthesis of fluorescent antagonist 4 enabled
affinity quantification (IC50s, nM) using flow cytometry
of P2Y14R-expressing CHO cells. p-F3C-phenyl-triazole 65 (32) was more potent than
a corresponding alkyne 11. Thus, additional triazolyl
derivatives were prepared, as guided by docking simulations, with
nonpolar aryl substituents favored. Although triazoles were less potent
than 3 (6), simpler synthesis facilitated further structural
optimization. Additionally, relative P2Y14R affinities
agreed with predicted binding of alkynyl and triazole analogues. These
triazoles, designed through a structure-based approach, can be assessed
in disease models.
Objective
To evaluate the association between Cushing syndrome and hypercoagulability in children.
Study design
A prospective, observational study was performed of 54 patients with Cushing syndrome, 15.1 ± 3.9 years, treated at the National Institutes of Health Clinical Center. Coagulation profiles were taken before and 6-12 months after surgery and compared with 18 normocortisolemic children, 13.7 ± 3.6 years.
Results
At baseline, patients with Cushing syndrome had greater levels of the procoagulant factor VIII (FVIII) vs controls (145 IU/dL ± 84 vs 99 ± 47, P = .04); 6-12 months after surgery, FVIII levels decreased to 111 ± 47, P = .05. Patients with Cushing syndrome had greater levels of the antifibrinolytic α2-antiplasmin, 96 ± 17% vs 82 ± 26%, P = .015. After surgery, antifibrinolytic α2-antiplasmin levels decreased to 82 ± 24%, P < .001. Anticoagulants were greater in patients with Cushing syndrome vs controls at baseline, including protein C (138 ± 41% vs 84 ± 25%, P < .001), protein S (94 ± 19% vs 74 ± 19%, P = .001), and antithrombin III (96 ± 18% vs 77 ± 13%, P < .0001). The 24-hour urinary free cortisol levels correlated positively with FVIII levels, r = 0.43, P = .004.
Conclusion
Children with Cushing syndrome had elevated procoagulants, antifibrinolytics, and anticoagulants at baseline compared with controls; normalization of coagulation measures was seen after surgical cure. Despite the increase in anticoagulants, hypercortisolemia is associated with a hypercoagulable state in children, as is the case in adults. This finding has potential implications for prevention of venous thromboembolism in children with Cushing syndrome.
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