J Med Chem.\u00a02022 Feb 24;65(4):3218-3228.\u00a0doi: 10.1021\/acs.jmedchem.1c01709.Epub 2022 Feb 4.<\/p>\n\n\n\n
Ilyas Berhane<\/a>,\u00a0Niyada Hin<\/a>,\u00a0Ajit G Thomas<\/a>,\u00a0Qian Huang<\/a>,\u00a0Chi Zhang<\/a>,\u00a0Vijayabhaskar Veeravalli<\/a>,\u00a0Ying Wu<\/a>,\u00a0Justin Ng<\/a>,\u00a0Jesse Alt<\/a>,\u00a0Camilo Rojas<\/a>,\u00a0Hiroe Hihara<\/a>\u00a01<\/a><\/sup>,\u00a0Mika Aoki<\/a>\u00a01<\/a><\/sup>,\u00a0Kyoko Yoshizawa<\/a>\u00a01<\/a><\/sup>,\u00a0Tomoki Nishioka<\/a>\u00a01<\/a><\/sup>,\u00a0Shuichi Suzuki<\/a>\u00a01<\/a><\/sup>,\u00a0Shao-Qiu He<\/a>,\u00a0Qi Peng<\/a>,\u00a0Yun Guan<\/a>,\u00a0Xinzhong Dong<\/a>,\u00a0Srinivasa N Raja<\/a>,\u00a0Barbara S Slusher<\/a>,\u00a0Rana Rais<\/a>,\u00a0Takashi Tsukamoto<\/a><\/p>\n\n\n\n Mas-related G protein-coupled receptor X1 (MRGPRX1) is a human sensory neuron-specific receptor and potential target for the treatment of pain. Positive allosteric modulators (PAMs) of MRGPRX1 have the potential to preferentially activate the receptors at the central terminals of primary sensory neurons and minimize itch side effects caused by peripheral activation. Using a high-throughput screening (HTS) hit, a series of thieno[2,3-d<\/em>]pyrimidine-based molecules were synthesized and evaluated as human MRGPRX1 PAMs in HEK293 cells stably transfected with human MrgprX1 gene. An iterative process to improve potency and metabolic stability led to the discovery of orally available 6-(tert<\/em>-butyl)-5-(3,4-dichlorophenyl)-4-(2-(trifluoromethoxy)phenoxy)thieno[2,3-d<\/em>]pyrimidine (1t<\/strong>), which can be distributed to the spinal cord, the presumed site of action, following oral administration. In a neuropathic pain model induced by sciatic nerve chronic constriction injury (CCI), compound 1t<\/strong>(100 mg\/kg, po) reduced behavioral heat hypersensitivity in humanized MRGPRX1 mice, demonstrating the therapeutic potential of MRGPRX1 PAMs in treating neuropathic pain.<\/p>\n\n\n\n J Med Chem.\u00a02022 Feb 24;65(4):3218-3228.\u00a0doi: 10.1021\/acs.jmedchem.1c01709.Epub 2022 Feb 4. Thieno[2,3- d]pyrimidine-Based Positive Allosteric Modulators of Human Mas-Related G Protein-Coupled Receptor X1 (MRGPRX1) Ilyas Berhane,\u00a0Niyada Hin,\u00a0Ajit G Thomas,\u00a0Qian Huang,\u00a0Chi Zhang,\u00a0Vijayabhaskar Veeravalli,\u00a0Ying Wu,\u00a0Justin Ng,\u00a0Jesse Alt,\u00a0Camilo Rojas,\u00a0Hiroe Hihara\u00a01,\u00a0Mika Aoki\u00a01,\u00a0Kyoko Yoshizawa\u00a01,\u00a0Tomoki Nishioka\u00a01,\u00a0Shuichi Suzuki\u00a01,\u00a0Shao-Qiu He,\u00a0Qi Peng,\u00a0Yun Guan,\u00a0Xinzhong Dong,\u00a0Srinivasa N Raja,\u00a0Barbara S Slusher,\u00a0Rana Rais,\u00a0Takashi Tsukamoto PMID: 35119273 DOI: 10.1021\/acs.jmedchem.1c01709 Abstract Mas-related G protein-coupled receptor […]<\/p>\n","protected":false},"author":1,"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\/2474"}],"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\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=2474"}],"version-history":[{"count":4,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/posts\/2474\/revisions"}],"predecessor-version":[{"id":2479,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/posts\/2474\/revisions\/2479"}],"wp:attachment":[{"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=2474"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=2474"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=2474"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}Abstract<\/h2>\n\n\n\n