Sandbox Reserved 895: Difference between revisions

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In 2008, Acucela Inc. partnered with Otsuka Pharmaceutical Company for the continued development of (''R'')-emixustat as a potential inhibitor of RPE65. Currently (''R'')-emixustat is in Phase III clinical trials in the United States for the potential treatment of Stargard's disease, a juvenile form of dry AMD. Additionally, (''R'')-emixustat is investigated as a potential therapy for diabetic retinopathy and diabetic macular edema. <ref> Maekawa H. Acucela Provides Update on Emixustat Phase 3 Clinical Trial in Patients With Stargardt Disease. BioSpace. 13 Feb 2020. Available from: https://www.biospace.com/article/releases/acucela-provides-update-on-emixustat-phase-3-clinical-trial-in-patients-with-stargardt-disease/ </ref>

==== '''[2.2.1.2] Clinical Trials ''' ====

Historically (''R'')-emixustat was tested as a possible treatment for dry AMD. In a Phase 1, dose-ranging clinical study of (''R'')-emixustat hydrochloride in healthy individuals the safety and tolerability of a 14-day course of either 5, 10, 20, 30 or 40 mg of (''R'')-emixustat was studied. A placebo in a 3 to 1 ratio was used. The results showed that (''R'')-emixustat was rapidly absorbed and very readily eliminated. Since the drug was rapidly eliminated, with a clearance of about 400% of that of hepatic blood flow, no significant accumulation of the drug was seen. Unfortunately, because of the high rate of elimination, the maximum concentration and the area under the curve was not significant from a clinical standpoint. Using the highest dose available, 40 mg, (''R'')-emixustat showed off-target effects and retinal toxicity liabilities. Using an electroretinogram, high dose (''R'')-emixustat inhibited the phototransduction process leading to blindness seen in LCA patients. As such (''R'')-emixustat was limited by both the minimum dose as well as the maximum dose. The use of (''R'')-emixustat in Phase IIb/III clinical trials failed to show clinical outcomes due to significant pharmacokinetic and pharmacodynamic limitations and thus was not approved by the FDA. Subsequent research is in progress to address the shortcomings of (''R'')-emixustat for the potential modulation of RPE65. <ref> DOI 24056528 </ref>

=== '''[2.2.2] Structural Interaction and Stereoselectivity''' ===

Zhang and colleagues determined the binding interactions between RPE65 and emixustat by looking at the protein-ligand complex under three different considerations. The three considerations were RPE65 with a racemic emixustat, RPE65 with pure (''R'')-emixustat and RPE65 with pure (''S'')-emixustat. With all three cases, residual maps showed the presence of bound palmitate in the active site with the carboxylate oxygen forming a monodentate coordinate bond with the iron ion. The hydroxyl moiety in emixustat interacted via a hydrogen bond with the hydroxyl moiety in Thr147 whereas the primary amine was involved in a polar interaction with the carboxylate groups of Glu148 as well as the bound palmitate ligand. Crystal structure that was obtained in the presence of the racemic mixture of emixustat showed that the electron density was consistent with exclusive binding of the (''R'')-isomer ('''Figure 1B''').

= References =

Sandbox Reserved 895: Difference between revisions

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@@ Line 82: / Line 82: @@
 [[Image:Figrue7_Emixustat.jpg|thumb|center|512 px|alt=Figure 7: Emixustat| '''Figure 7:''' (''R'')-Emixustat]]
+In 2008, Acucela Inc. partnered with Otsuka Pharmaceutical Company for the continued development of (''R'')-emixustat as a potential inhibitor of RPE65. Currently (''R'')-emixustat is in Phase III clinical trials in the United States for the potential treatment of Stargard's disease, a juvenile form of dry AMD. Additionally, (''R'')-emixustat is investigated as a potential therapy for diabetic retinopathy and diabetic macular edema. <ref> Maekawa H. Acucela Provides Update on Emixustat Phase 3 Clinical Trial in Patients With Stargardt Disease. BioSpace. 13 Feb 2020. Available from: https://www.biospace.com/article/releases/acucela-provides-update-on-emixustat-phase-3-clinical-trial-in-patients-with-stargardt-disease/ </ref>
+==== '''[2.2.1.2] Clinical Trials ''' ====
+Historically (''R'')-emixustat was tested as a possible treatment for dry AMD. In a Phase 1, dose-ranging clinical study of (''R'')-emixustat hydrochloride in healthy individuals the safety and tolerability of a 14-day course of either 5, 10, 20, 30 or 40 mg of (''R'')-emixustat was studied. A placebo in a 3 to 1 ratio was used. The results showed that (''R'')-emixustat was rapidly absorbed and very readily eliminated. Since the drug was rapidly eliminated, with a clearance of about 400% of that of hepatic blood flow, no significant accumulation of the drug was seen. Unfortunately, because of the high rate of elimination, the maximum concentration and the area under the curve was not significant from a clinical standpoint. Using the highest dose available, 40 mg, (''R'')-emixustat showed off-target effects and retinal toxicity liabilities. Using an electroretinogram, high dose (''R'')-emixustat inhibited the phototransduction process leading to blindness seen in LCA patients. As such (''R'')-emixustat was limited by both the minimum dose as well as the maximum dose. The use of (''R'')-emixustat in Phase IIb/III clinical trials failed to show clinical outcomes due to significant pharmacokinetic and pharmacodynamic limitations and thus was not approved by the FDA. Subsequent research is in progress to address the shortcomings of (''R'')-emixustat for the potential modulation of RPE65. <ref> DOI 24056528 </ref>
+=== '''[2.2.2] Structural Interaction and Stereoselectivity''' ===
+Zhang and colleagues determined the binding interactions between RPE65 and emixustat by looking at the protein-ligand complex under three different considerations. The three considerations were RPE65 with a racemic emixustat, RPE65 with pure (''R'')-emixustat and RPE65 with pure (''S'')-emixustat. With all three cases, residual maps showed the presence of bound palmitate in the active site with the carboxylate oxygen forming a monodentate coordinate bond with the iron ion. The hydroxyl moiety in emixustat interacted via a hydrogen bond with the hydroxyl moiety in Thr147 whereas the primary amine was involved in a polar interaction with the carboxylate groups of Glu148 as well as the bound palmitate ligand. Crystal structure that was obtained in the presence of the racemic mixture of emixustat showed that the electron density was consistent with exclusive binding of the (''R'')-isomer ('''Figure 1B''').
 = References =
 <references/>