{"id":19358,"date":"2018-01-14T09:07:38","date_gmt":"2018-01-14T09:07:38","guid":{"rendered":"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/?p=19358"},"modified":"2018-05-18T10:00:58","modified_gmt":"2018-05-18T09:00:58","slug":"silicon-drug-analogues","status":"publish","type":"post","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=19358","title":{"rendered":"Silicon drug analogues."},"content":{"rendered":"
\n

I don’t normally write about the pharmaceutical industry, but I was intrigued by several posts by Derek Lowe (who does cover this area) on the topic of creating new drugs by deuterating existing ones. Thus he covered<\/a> the first deuterated drug receiving FDA approval last year, having first reviewed<\/a> the concept back in 2009. So when someone introduced me to sila-haloperidol<\/strong>, I checked to see if Derek had written about it. Apparently not, so here are a few details.<\/p>\n

\"\"<\/a><\/p>\n

The idea appears to take a well-known drug, in this case haloperidol<\/a> and selectively replacing a carbon atom with a silicon atom to form silahaloperidol.[1]<\/a><\/span> The compound was actually reported in 2004 (see data citation\u00a010.5517\/cc7yhc0<\/a>) but its drug-like properties were only reported four years later in 2008. Haloperidol itself has some undesirable side-effects, including those due to the metabolic products of the drug and so there are certainly reasons for trying to reduce these. Here are the main conclusions:<\/p>\n

    \n
  1. The sila drug shows a significantly higher affinity for hD2<\/sub> receptors (Table 1).<\/li>\n
  2. Silahaloperidol exhibits higher subtype selectivity\u00a0at dopamine and \u03c3 receptors<\/li>\n
  3. The substitution by silicon has little effect on physico-chemical profiles<\/li>\n
  4. The in-vivo<\/em> half-life of the sila analogue was 3.6 times shorter (~18 minutes).<\/li>\n
  5. An almost three-fold inhibitory effect against CYP3A4 was noted.<\/li>\n
  6. The sila-drug displayed “a completely altered metabolic fate while otherwise maintaining a similar pharmacokinetic profile”.<\/li>\n<\/ol>\n

    These do seem to add up to a promising route for optimising drug activities. The authors themselves note the “great potential” for drug design. A review in 2017[2]<\/a><\/span> concurs. So along with deuterated drugs, perhaps siladrugs are ones to watch in the future!<\/p>\n

    \n

    Postscript. More reports of silicon analogues.[3]<\/a><\/span><\/p>\n

    References<\/h2>\n
    1. R. Tacke, F. Popp, B. M\u00fcller, B. Theis, C. Burschka, A. Hamacher, M. Kassack, D. Schepmann, B. W\u00fcnsch, U. Jurva, and E. Wellner, \"Sila\u2010Haloperidol, a Silicon Analogue of the Dopamine (D\n <sub>2<\/sub>\n ) Receptor Antagonist Haloperidol: Synthesis, Pharmacological Properties, and Metabolic Fate\", ChemMedChem<\/i>, vol. 3, pp. 152-164, 2008. https:\/\/doi.org\/10.1002\/cmdc.200700205<\/a>\n\n<\/li>\n
    2. R. Ramesh, and D.S. Reddy, \"Quest for Novel Chemical Entities through Incorporation of Silicon in Drug Scaffolds\", Journal of Medicinal Chemistry<\/i>, vol. 61, pp. 3779-3798, 2017. https:\/\/doi.org\/10.1021\/acs.jmedchem.7b00718<\/a>\n\n<\/li>\n
    3. S.J. Barraza, and S.E. Denmark, \"Synthesis, Reactivity, Functionalization, and ADMET Properties of Silicon-Containing Nitrogen Heterocycles\", Journal of the American Chemical Society<\/i>, vol. 140, pp. 6668-6684, 2018. https:\/\/doi.org\/10.1021\/jacs.8b03187<\/a>\n\n<\/li>\n<\/ol>\n\n<\/div> ","protected":false},"excerpt":{"rendered":"

      I don’t normally write about the pharmaceutical industry, but I was intrigued by several posts by Derek Lowe (who does cover this area) on the topic of creating new drugs by deuterating existing ones. Thus he covered the first deuterated drug receiving FDA approval last year, having first reviewed the concept back in 2009. So […]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"jetpack_post_was_ever_published":false,"_jetpack_newsletter_access":"","_jetpack_dont_email_post_to_subs":false,"_jetpack_newsletter_tier_id":0,"_jetpack_memberships_contains_paywalled_content":false,"_jetpack_memberships_contains_paid_content":false,"activitypub_content_warning":"","activitypub_content_visibility":"","activitypub_max_image_attachments":5,"activitypub_interaction_policy_quote":"anyone","activitypub_status":"","footnotes":"","jetpack_publicize_message":"","jetpack_publicize_feature_enabled":true,"jetpack_social_post_already_shared":true,"jetpack_social_options":{"image_generator_settings":{"template":"highway","default_image_id":0,"font":"","enabled":false},"version":2}},"categories":[1],"tags":[1395,1313,2353,2355,2357,2359,2350,2352,2348,2356,2360,2358,2354,2349,2361,2351],"ppma_author":[2661],"class_list":["post-19358","post","type-post","status-publish","format-standard","hentry","category-general","tag-chemistry","tag-derek-lowe","tag-deuterated-drug","tag-drug","tag-drug-design","tag-fda","tag-food-and-drug-administration","tag-haloperidol","tag-health","tag-health-medical-pharmaceuticals","tag-htc-hd2-smartphone","tag-metabolic-products","tag-pharmaceutical-industry","tag-pharmacy","tag-physico-chemical-profiles","tag-united-states-public-health-service"],"yoast_head":"\nSilicon drug analogues. - Henry Rzepa's Blog<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=19358\" \/>\n<meta property=\"og:locale\" content=\"en_GB\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Silicon drug analogues. - Henry Rzepa's Blog\" \/>\n<meta property=\"og:description\" content=\"I don’t normally write about the pharmaceutical industry, but I was intrigued by several posts by Derek Lowe (who does cover this area) on the topic of creating new drugs by deuterating existing ones. Thus he covered the first deuterated drug receiving FDA approval last year, having first reviewed the concept back in 2009. So […]\" \/>\n<meta property=\"og:url\" content=\"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=19358\" \/>\n<meta property=\"og:site_name\" content=\"Henry Rzepa's Blog\" \/>\n<meta property=\"article:published_time\" content=\"2018-01-14T09:07:38+00:00\" \/>\n<meta property=\"article:modified_time\" content=\"2018-05-18T09:00:58+00:00\" \/>\n<meta property=\"og:image\" content=\"http:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2018\/01\/silahaloperidol-page001.svg\" \/>\n<meta name=\"author\" content=\"Henry Rzepa\" \/>\n<meta name=\"twitter:card\" content=\"summary_large_image\" \/>\n<meta name=\"twitter:label1\" content=\"Written by\" \/>\n\t<meta name=\"twitter:data1\" content=\"Henry Rzepa\" \/>\n\t<meta name=\"twitter:label2\" content=\"Estimated reading time\" \/>\n\t<meta name=\"twitter:data2\" content=\"1 minute\" \/>\n<!-- \/ Yoast SEO plugin. -->","yoast_head_json":{"title":"Silicon drug analogues. - Henry Rzepa's Blog","robots":{"index":"index","follow":"follow","max-snippet":"max-snippet:-1","max-image-preview":"max-image-preview:large","max-video-preview":"max-video-preview:-1"},"canonical":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=19358","og_locale":"en_GB","og_type":"article","og_title":"Silicon drug analogues. - Henry Rzepa's Blog","og_description":"I don’t normally write about the pharmaceutical industry, but I was intrigued by several posts by Derek Lowe (who does cover this area) on the topic of creating new drugs by deuterating existing ones. Thus he covered the first deuterated drug receiving FDA approval last year, having first reviewed the concept back in 2009. So […]","og_url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=19358","og_site_name":"Henry Rzepa's Blog","article_published_time":"2018-01-14T09:07:38+00:00","article_modified_time":"2018-05-18T09:00:58+00:00","og_image":[{"url":"http:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2018\/01\/silahaloperidol-page001.svg","type":"","width":"","height":""}],"author":"Henry Rzepa","twitter_card":"summary_large_image","twitter_misc":{"Written by":"Henry Rzepa","Estimated reading time":"1 minute"},"schema":{"@context":"https:\/\/schema.org","@graph":[{"@type":"Article","@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=19358#article","isPartOf":{"@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=19358"},"author":{"name":"Henry Rzepa","@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/#\/schema\/person\/2b40f7b9c872a4dc1547e040a11b6281"},"headline":"Silicon drug analogues.","datePublished":"2018-01-14T09:07:38+00:00","dateModified":"2018-05-18T09:00:58+00:00","mainEntityOfPage":{"@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=19358"},"wordCount":288,"commentCount":0,"image":{"@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=19358#primaryimage"},"thumbnailUrl":"http:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2018\/01\/silahaloperidol-page001.svg","keywords":["Chemistry","Derek Lowe","Deuterated drug","Drug","drug design","FDA","Food and Drug Administration","Haloperidol","Health","Health\/Medical\/Pharmaceuticals","HTC HD2 Smartphone","metabolic products","Pharmaceutical industry","Pharmacy","physico-chemical profiles","United States Public Health Service"],"articleSection":["General"],"inLanguage":"en-GB","potentialAction":[{"@type":"CommentAction","name":"Comment","target":["https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=19358#respond"]}]},{"@type":"WebPage","@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=19358","url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=19358","name":"Silicon drug analogues. - Henry Rzepa's Blog","isPartOf":{"@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/#website"},"primaryImageOfPage":{"@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=19358#primaryimage"},"image":{"@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=19358#primaryimage"},"thumbnailUrl":"http:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2018\/01\/silahaloperidol-page001.svg","datePublished":"2018-01-14T09:07:38+00:00","dateModified":"2018-05-18T09:00:58+00:00","author":{"@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/#\/schema\/person\/2b40f7b9c872a4dc1547e040a11b6281"},"breadcrumb":{"@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=19358#breadcrumb"},"inLanguage":"en-GB","potentialAction":[{"@type":"ReadAction","target":["https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=19358"]}]},{"@type":"ImageObject","inLanguage":"en-GB","@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=19358#primaryimage","url":"http:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2018\/01\/silahaloperidol-page001.svg","contentUrl":"http:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2018\/01\/silahaloperidol-page001.svg"},{"@type":"BreadcrumbList","@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=19358#breadcrumb","itemListElement":[{"@type":"ListItem","position":1,"name":"Home","item":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog"},{"@type":"ListItem","position":2,"name":"Silicon drug analogues."}]},{"@type":"WebSite","@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/#website","url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/","name":"Henry Rzepa's Blog","description":"Chemistry with a twist","potentialAction":[{"@type":"SearchAction","target":{"@type":"EntryPoint","urlTemplate":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?s={search_term_string}"},"query-input":{"@type":"PropertyValueSpecification","valueRequired":true,"valueName":"search_term_string"}}],"inLanguage":"en-GB"},{"@type":"Person","@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/#\/schema\/person\/2b40f7b9c872a4dc1547e040a11b6281","name":"Henry Rzepa","image":{"@type":"ImageObject","inLanguage":"en-GB","@id":"https:\/\/secure.gravatar.com\/avatar\/897b6740f7f599bca7942cdf7d7914af5988937ae0e3869ab09aebb87f26a731?s=96&d=blank&r=g370be3a7397865e4fd161aefeb0a5a85","url":"https:\/\/secure.gravatar.com\/avatar\/897b6740f7f599bca7942cdf7d7914af5988937ae0e3869ab09aebb87f26a731?s=96&d=blank&r=g","contentUrl":"https:\/\/secure.gravatar.com\/avatar\/897b6740f7f599bca7942cdf7d7914af5988937ae0e3869ab09aebb87f26a731?s=96&d=blank&r=g","caption":"Henry Rzepa"},"description":"Henry Rzepa is Emeritus Professor of Computational Chemistry at Imperial College London.","sameAs":["https:\/\/orcid.org\/0000-0002-8635-8390"],"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?author=1"}]}},"jetpack_publicize_connections":[],"jetpack_featured_media_url":"","jetpack_sharing_enabled":true,"jetpack_shortlink":"https:\/\/wp.me\/pDef7-52e","jetpack-related-posts":[{"id":17089,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=17089","url_meta":{"origin":19358,"position":0},"title":"Hydrogen bonding to chloroform.","author":"Henry Rzepa","date":"November 14, 2016","format":false,"excerpt":"Chloroform, often in the deuterated form CDCl3, is a very common solvent for NMR and other types of spectroscopy. Quantum mechanics\u00a0is increasingly used to calculate such spectra to aid assignment and the solvent is here normally simulated as a continuum rather than by explicit inclusion of one or more chloroform\u2026","rel":"","context":"In "crystal_structure_mining"","block_context":{"text":"crystal_structure_mining","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=1745"},"img":{"alt_text":"","src":"","width":0,"height":0},"classes":[]},{"id":18399,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=18399","url_meta":{"origin":19358,"position":1},"title":"CH\u22c5\u22c5\u22c5\u03c0 Interactions between methyl and carbonyl groups in proteins: a small molecule check.","author":"Henry Rzepa","date":"May 29, 2017","format":false,"excerpt":"Derek Lowe highlights a recent article postulating\u00a0CH\u22c5\u22c5\u22c5\u03c0 interactions in proteins. Here I report a quick check using the small molecule crystal structure database (CSD). The search query (DOI:\u00a010.14469\/hpc\/2594)\u00a0is shown below. The distance refers to that between the (normalised) position of a hydrogen on a 4-coordinated carbon atom and the centroid\u2026","rel":"","context":"In "crystal_structure_mining"","block_context":{"text":"crystal_structure_mining","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=1745"},"img":{"alt_text":"","src":"https:\/\/i0.wp.com\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2017\/05\/152-1024x637.jpg?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":17333,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=17333","url_meta":{"origin":19358,"position":2},"title":"Ritonavir: a look at a famous example of conformational polymorphism.","author":"Henry Rzepa","date":"January 2, 2017","format":false,"excerpt":"Here is an inside peek at another one of Derek Lowe's 250 milestones in chemistry, the polymorphism of Ritonavir.\u00a0The story in a nutshell concerns one of a pharma company's worst nightmares; a drug which has been successfully brought to market unexpectedly\u00a0\"changes\" after a few years on market to a less\u2026","rel":"","context":"In "Interesting chemistry"","block_context":{"text":"Interesting chemistry","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=4"},"img":{"alt_text":"","src":"","width":0,"height":0},"classes":[]},{"id":14740,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=14740","url_meta":{"origin":19358,"position":3},"title":"How to stop (some) acetals hydrolysing.","author":"Henry Rzepa","date":"November 12, 2015","format":false,"excerpt":"Derek Lowe has a recent post entitled \"Another Funny-Looking Structure Comes Through\". He cites a recent medchem article in which the following acetal sub-structure appears in a promising drug candidate (blue component below). His point is that orally taken drugs have to survive acid (green below) encountered in the stomach,\u2026","rel":"","context":"In "reaction mechanism"","block_context":{"text":"reaction mechanism","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=1086"},"img":{"alt_text":"","src":"","width":0,"height":0},"classes":[]},{"id":13248,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=13248","url_meta":{"origin":19358,"position":4},"title":"A convincing example of the need for data repositories. FAIR Data.","author":"Henry Rzepa","date":"January 15, 2015","format":false,"excerpt":"Derek Lowe in his In the Pipeline blog is famed for spotting unusual claims in the literature and subjecting them to analysis. This one is entitled\u00a0Odd Structures, Subjected to Powerful Computations. He looks at this image below, and finds the structures represented there might be a mistake, based on his\u2026","rel":"","context":"In "Chemical IT"","block_context":{"text":"Chemical IT","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=2"},"img":{"alt_text":"","src":"","width":0,"height":0},"classes":[]},{"id":25486,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=25486","url_meta":{"origin":19358,"position":5},"title":"Octafluorocubane radical anion – where does the extra electron sit?","author":"Henry Rzepa","date":"August 29, 2022","format":false,"excerpt":"Derek Lowe reports the story that the recently synthesized octafluorocubane can absorb one electron to form a radical anion - an electron in a cube. So I thought it would be fun to compute exactly where that electron sits! A\u00a0\u03c9B97XD\/Def2-TZVPPD\/SCRF=chloroform\u00a0calculation (DOI: 10.14469\/hpc\/11090) is carried out on the neutral system (optimizing\u2026","rel":"","context":"With 10 comments","block_context":{"text":"With 10 comments","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=25486#comments"},"img":{"alt_text":"","src":"https:\/\/i0.wp.com\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2022\/08\/perfluorotetrahedrane-anion_den_sub.png?resize=350%2C200&ssl=1","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2022\/08\/perfluorotetrahedrane-anion_den_sub.png?resize=350%2C200&ssl=1 1x, https:\/\/i0.wp.com\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2022\/08\/perfluorotetrahedrane-anion_den_sub.png?resize=525%2C300&ssl=1 1.5x"},"classes":[]}],"jetpack_likes_enabled":false,"authors":[{"term_id":2661,"user_id":1,"is_guest":0,"slug":"admin","display_name":"Henry Rzepa","avatar_url":"https:\/\/secure.gravatar.com\/avatar\/897b6740f7f599bca7942cdf7d7914af5988937ae0e3869ab09aebb87f26a731?s=96&d=blank&r=g","0":null,"1":"","2":"","3":"","4":"","5":"","6":"","7":"","8":""}],"_links":{"self":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/19358","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=19358"}],"version-history":[{"count":7,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/19358\/revisions"}],"predecessor-version":[{"id":19710,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/19358\/revisions\/19710"}],"wp:attachment":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=19358"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=19358"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=19358"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fppma_author&post=19358"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}