{"id":3772,"date":"2026-07-03T09:33:15","date_gmt":"2026-07-03T00:33:15","guid":{"rendered":"https:\/\/misterx95.myds.me\/wordpress\/?p=3772"},"modified":"2026-07-03T09:33:16","modified_gmt":"2026-07-03T00:33:16","slug":"development-of-a-clinically-viable-mrgprx4-inverse-agonist-for-cholestatic-itch-treatment","status":"publish","type":"post","link":"https:\/\/misterx95.myds.me\/wordpress\/?p=3772","title":{"rendered":"Development of a clinically viable MRGPRX4 inverse agonist for cholestatic itch treatment."},"content":{"rendered":"\n<p>2026.07.03<\/p>\n\n\n\n<p>Abstract<\/p>\n\n\n\n<p class=\"has-text-align-left\">Chronic itch, particularly in cholestatic and uremic conditions, poses<br>a notable clinical burden, yet treatment options remain inadequate.<br>MRGPRX4 (hX4), a bile-acid-sensing G-protein-coupled receptor<br>predominantly expressed in human sensory neurons, has emerged<br>as a critical mediator of cholestatic pruritus. Here we identified and<br>characterized HEP-50768, a potent and selective small-molecule inverse<br>agonist of hX4 through high-throughput screening and structure\u2013activity<br>optimization. Structural elucidation through cryo-electron microscopy of<br>the hX4\u2013inverse agonist complex structure revealed the unique binding<br>mode and inhibitory mechanism of HEP-50768. In hX4-humanized rats,<br>HEP-50768 robustly suppressed bile-acid-induced pruritic behaviors.<br>Comprehensive preclinical absorption, distribution, metabolism, excretion<br>and safety profiling was performed in both rats and monkeys, and these<br>findings establish HEP-50768 as a promising therapeutic candidate for<br>chronic itch, supporting its advancement to clinical evaluation.<\/p>\n\n\n\n<div class=\"wp-block-file\"><object class=\"wp-block-file__embed\" data=\"https:\/\/misterx95.myds.me\/wordpress\/wp-content\/uploads\/2026\/07\/Development-of-a-clinically-viable-MRGPRX4-inverse-agonist-for-cholestatic-itch-treatment.pdf\" type=\"application\/pdf\" style=\"width:100%;height:600px\" aria-label=\"Embed of Development-of-a-clinically-viable-MRGPRX4-inverse-agonist-for-cholestatic-itch-treatment.\"><\/object><a id=\"wp-block-file--media-e7c169f6-47f2-4d5a-8bb8-181279082ded\" href=\"https:\/\/misterx95.myds.me\/wordpress\/wp-content\/uploads\/2026\/07\/Development-of-a-clinically-viable-MRGPRX4-inverse-agonist-for-cholestatic-itch-treatment.pdf\">Development-of-a-clinically-viable-MRGPRX4-inverse-agonist-for-cholestatic-itch-treatment<\/a><a href=\"https:\/\/misterx95.myds.me\/wordpress\/wp-content\/uploads\/2026\/07\/Development-of-a-clinically-viable-MRGPRX4-inverse-agonist-for-cholestatic-itch-treatment.pdf\" class=\"wp-block-file__button wp-element-button\" download aria-describedby=\"wp-block-file--media-e7c169f6-47f2-4d5a-8bb8-181279082ded\">Download<\/a><\/div>\n\n\n\n<div class=\"wp-block-file\"><object class=\"wp-block-file__embed\" data=\"https:\/\/misterx95.myds.me\/wordpress\/wp-content\/uploads\/2026\/07\/Supplementary-of-development-of-a-clinically-viable-MRGPRX4-inverse-agonist.pdf\" type=\"application\/pdf\" style=\"width:100%;height:600px\" aria-label=\"Embed of Supplementary-of-development-of-a-clinically-viable-MRGPRX4-inverse-agonist.\"><\/object><a id=\"wp-block-file--media-df989acd-86b5-4b75-a6c5-91183a13fe28\" href=\"https:\/\/misterx95.myds.me\/wordpress\/wp-content\/uploads\/2026\/07\/Supplementary-of-development-of-a-clinically-viable-MRGPRX4-inverse-agonist.pdf\">Supplementary-of-development-of-a-clinically-viable-MRGPRX4-inverse-agonist<\/a><a href=\"https:\/\/misterx95.myds.me\/wordpress\/wp-content\/uploads\/2026\/07\/Supplementary-of-development-of-a-clinically-viable-MRGPRX4-inverse-agonist.pdf\" class=\"wp-block-file__button wp-element-button\" download aria-describedby=\"wp-block-file--media-df989acd-86b5-4b75-a6c5-91183a13fe28\">Download<\/a><\/div>\n","protected":false},"excerpt":{"rendered":"<p>2026.07.03 Abstract Chronic itch, particularly in cholestatic and uremic conditions, posesa notable clinical burden, yet treatment options remain inadequate.MRGPRX4 (hX4), a bile-acid-sensing G-protein-coupled receptorpredominantly expressed in human sensory neurons, has emergedas a critical mediator of cholestatic pruritus. Here we identified andcharacterized HEP-50768, a potent and selective small-molecule inverseagonist of hX4 through high-throughput screening and structure\u2013activityoptimization. [&hellip;]<\/p>\n","protected":false},"author":27,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"site-sidebar-layout":"default","site-content-layout":"","ast-site-content-layout":"","site-content-style":"default","site-sidebar-style":"default","ast-global-header-display":"","ast-banner-title-visibility":"","ast-main-header-display":"","ast-hfb-above-header-display":"","ast-hfb-below-header-display":"","ast-hfb-mobile-header-display":"","site-post-title":"","ast-breadcrumbs-content":"","ast-featured-img":"","footer-sml-layout":"","theme-transparent-header-meta":"","adv-header-id-meta":"","stick-header-meta":"","header-above-stick-meta":"","header-main-stick-meta":"","header-below-stick-meta":"","astra-migrate-meta-layouts":"default","ast-page-background-enabled":"default","ast-page-background-meta":{"desktop":{"background-color":"var(--ast-global-color-4)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"ast-content-background-meta":{"desktop":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}}},"categories":[1],"tags":[],"_links":{"self":[{"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/posts\/3772"}],"collection":[{"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/users\/27"}],"replies":[{"embeddable":true,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=3772"}],"version-history":[{"count":1,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/posts\/3772\/revisions"}],"predecessor-version":[{"id":3775,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/posts\/3772\/revisions\/3775"}],"wp:attachment":[{"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=3772"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=3772"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=3772"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}