Frontiers in Medicinal Chemistry

Volume: 1

The Design of Competitive, Small-molecule Inhibitors of Coagulation Factor Xa

Author(s): Henry W. Pauls, William R. Ewing and Yong Mi Choi-Sledeski

Pp: 129-152 (24)

DOI: 10.2174/978160805204210401010129

* (Excluding Mailing and Handling)

Abstract

The last five years has seen an explosion of research into inhibitors of Factor Xa as potential antithrombotic agents. Aventis Pharma through its founder company Rhone-Poulenc Rorer was a participant in this effort and contributed significantly to the discovery of new inhibitors in recent years. This chapter traces the systematic development of the former Rhone-Poulenc Rorer factor Xa program from conception to the realization of potent, orally bioavailable inhibitors with exquisite selectivity against other serine proteases. The work on b- aminoesters described in Part 1 culminates in the development of FXV673 (Ki = 0.5 nM), an effective anticoagulant for acute indications. Part 2.2 details the de novo design of a pyrrolidinone series of inhibitors, within which a group of efficacious i.v. agents were identified (e.g RPR130737, Ki = 2 nM). The first active and bioavailable benzamidine isostere i.e. the 1-aminoisoquinoline (RPR208815, Ki = 22 nM) was discovered on the pyrrolidinone scaffold (Part 2.3). Ultimately a variety of benzamidine mimics were explored and incorporated into the ketopiperazine series (Part 3); the 6-substituted aminoquinazolines were found to be subnanomolar against factor Xa and highly selective. The azaindole moiety stands out as imparting favorable pharmacokinetic properties to the sulfonamido-ketopiperazines; RPR209685, a potent representative (Ki = 1 nM), was shown to be orally efficacious in the dog.

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      • 11. app/Models/ContentAccess.php:647
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      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ChapterController.php:1518
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 59769557 and j.to_ip >=59769557 )) and ((j.from_date <= 1739834969 and j.to_date >= 1739834969 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 2270) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 59769557 and j.to_ip >=59769557 )) and ((j.from_date <= 1739834969 and j.to_date >= 1739834969 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 2270) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 59769557 and j.to_ip >=59769557 )) and ((j.from_date <= 1739834969 and j.to_date >= 1739834969 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 2270)
      510μsalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ChapterController.php:1549
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select b.banner_link, b.banner_name, b.banner_script, b.banner_remarks, b.banner_file_name, b.banner_placement, bd.content_type, bd.content_id from `tbl_banner` as `b` inner join `tbl_banner_detail` as `bd` on `bd`.`banner_id` = `b`.`banner_id` inner join `users` as `u` on `u`.`id` = `b`.`updated_by` where `b`.`banner_ebook` = 1 and `bd`.`content_type` = 'B' and `bd`.`content_id` = 948 and `b`.`banner_from_date` <= 1739834969 and `b`.`banner_to_date` >= 1739834969 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.05msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: B
      • 2: 948
      • 3: 1739834969
      • 4: 1739834969
      • 5: A
      Backtrace
      • 13. app/Models/Banner.php:95
      • 14. app/Http/helpers.php:404
      • 17. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 18. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    • select count(*) as aggregate from `uc_cart_products` where cart_id='f1d1a25252c4cb0a1883ef9f872cf3bb'
      190μsalphaeurekaselec_live_10_06_2022Cart.php#271
      Backtrace
      • 15. app/Models/Cart.php:271
      • 16. view::layouts._header:260
      • 18. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 20. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    App\Models\Chapter
    1Chapter.php#?
    App\Models\Ebook
    1Ebook.php#?
        _token
        DQx0rJiXra95UXuQn77Nvq88XgAkKCN4WW5p8RKd
        uc_cart_id
        f1d1a25252c4cb0a1883ef9f872cf3bb
        _previous
        array:1 [ "url" => "https://alpha.eurekaselect.com/chapter/2270" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /chapter/2270
        status_code
        200
        
        status_text
        OK
        format
        html
        content_type
        text/html; charset=UTF-8
        request_query
        []
        
        request_request
        []
        
        request_headers
        0 of 0
        array:16 [ "x-https" => array:1 [ 0 => "1" ] "host" => array:1 [ 0 => "alpha.eurekaselect.com" ] "priority" => array:1 [ 0 => "u=0, i" ] "accept-encoding" => array:1 [ 0 => "gzip, deflate, br, zstd" ] "sec-fetch-dest" => array:1 [ 0 => "document" ] "sec-fetch-user" => array:1 [ 0 => "?1" ] "sec-fetch-mode" => array:1 [ 0 => "navigate" ] "sec-fetch-site" => array:1 [ 0 => "none" ] "accept" => array:1 [ 0 => "text/html,application/xhtml+xml,application/xml;q=0.9,image/avif,image/webp,image/apng,*/*;q=0.8,application/signed-exchange;v=b3;q=0.7" ] "user-agent" => array:1 [ 0 => "Mozilla/5.0 AppleWebKit/537.36 (KHTML, like Gecko; compatible; ClaudeBot/1.0; +claudebot@anthropic.com)" ] "upgrade-insecure-requests" => array:1 [ 0 => "1" ] "sec-ch-ua-platform" => array:1 [ 0 => ""Windows"" ] "sec-ch-ua-mobile" => array:1 [ 0 => "?0" ] "sec-ch-ua" => array:1 [ 0 => ""HeadlessChrome";v="129", "Not=A?Brand";v="8", "Chromium";v="129"" ] "cache-control" => array:1 [ 0 => "no-cache" ] "pragma" => array:1 [ 0 => "no-cache" ] ]
        request_cookies
        []
        
        response_headers
        0 of 0
        array:5 [ "content-type" => array:1 [ 0 => "text/html; charset=UTF-8" ] "cache-control" => array:1 [ 0 => "no-cache, private" ] "date" => array:1 [ 0 => "Mon, 17 Feb 2025 23:29:29 GMT" ] "set-cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6IkFRNWNBZWZnK3k0V3F2Y25wZDBnMVE9PSIsInZhbHVlIjoiZkI4bkp0ZUJ0UHlCTmhJQnNBc2xoVy91VktnbUswTlFVZDFzMU9ZUW03NTVOSTkrNHRpTjZRZVQ0QWIvWjJXWUtRYzlRR1BCemhPMHRTd3p1dlh1OHFtMGYxMytodU1ONm8ycDQ5aWo5RnBtRytNNmpuTGNScFVab01hcFNia0IiLCJtYWMiOiI5OTIwNTY1Y2EzOWQwMTVjYjJmYzBiZjMzNDgwYzU3ZTZlMzYzMmJkNDQ3MmQ5YzZiNDMxMjIzN2MyYTE2ODg2IiwidGFnIjoiIn0%3D; expires=Thu, 20 Feb 2025 11:29:29 GMT; Max-Age=216000; path=/; secure; samesite=laxXSRF-TOKEN=eyJpdiI6IkFRNWNBZWZnK3k0V3F2Y25wZDBnMVE9PSIsInZhbHVlIjoiZkI4bkp0ZUJ0UHlCTmhJQnNBc2xoVy91VktnbUswTlFVZDFzMU9ZUW03NTVOSTkrNHRpTjZRZVQ0QWIvWjJXWUtRYzlRR" 1 => "alphaeurekaselectnet_session=eyJpdiI6InhWQ2MydFJYbE02b014TGdUS2RSMEE9PSIsInZhbHVlIjoiSFNEN0ZmdDlzY2I0blp2WTQ0YytRcHpkdlA4YW9MVTUwbHdBSncySXJ4Qk5hOFhIOUZEVk9XQnZpd2xJNG1wZCtMYlNGd3ZYVFcxVEordU92c3luc1RsNnV2emNveTNzdlF1NE1XNWxiaW56NjlBQzNjWnE2Y0UzQzJOS0xmMWIiLCJtYWMiOiI1MmNiMDYxZWI4ZGU5ZWNmNTNmZjExNTRmYWVkMTE2NDU0YTRhN2RhY2Y5NTlkZWU5ODg1YWNjMjBkNWRkMTJmIiwidGFnIjoiIn0%3D; path=/; secure; httponly; samesite=laxalphaeurekaselectnet_session=eyJpdiI6InhWQ2MydFJYbE02b014TGdUS2RSMEE9PSIsInZhbHVlIjoiSFNEN0ZmdDlzY2I0blp2WTQ0YytRcHpkdlA4YW9MVTUwbHdBSncySXJ4Qk5hOFhIOUZEVk9XQnZ" ] "Set-Cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6IkFRNWNBZWZnK3k0V3F2Y25wZDBnMVE9PSIsInZhbHVlIjoiZkI4bkp0ZUJ0UHlCTmhJQnNBc2xoVy91VktnbUswTlFVZDFzMU9ZUW03NTVOSTkrNHRpTjZRZVQ0QWIvWjJXWUtRYzlRR1BCemhPMHRTd3p1dlh1OHFtMGYxMytodU1ONm8ycDQ5aWo5RnBtRytNNmpuTGNScFVab01hcFNia0IiLCJtYWMiOiI5OTIwNTY1Y2EzOWQwMTVjYjJmYzBiZjMzNDgwYzU3ZTZlMzYzMmJkNDQ3MmQ5YzZiNDMxMjIzN2MyYTE2ODg2IiwidGFnIjoiIn0%3D; expires=Thu, 20-Feb-2025 11:29:29 GMT; path=/; secureXSRF-TOKEN=eyJpdiI6IkFRNWNBZWZnK3k0V3F2Y25wZDBnMVE9PSIsInZhbHVlIjoiZkI4bkp0ZUJ0UHlCTmhJQnNBc2xoVy91VktnbUswTlFVZDFzMU9ZUW03NTVOSTkrNHRpTjZRZVQ0QWIvWjJXWUtRYzlRR" 1 => "alphaeurekaselectnet_session=eyJpdiI6InhWQ2MydFJYbE02b014TGdUS2RSMEE9PSIsInZhbHVlIjoiSFNEN0ZmdDlzY2I0blp2WTQ0YytRcHpkdlA4YW9MVTUwbHdBSncySXJ4Qk5hOFhIOUZEVk9XQnZpd2xJNG1wZCtMYlNGd3ZYVFcxVEordU92c3luc1RsNnV2emNveTNzdlF1NE1XNWxiaW56NjlBQzNjWnE2Y0UzQzJOS0xmMWIiLCJtYWMiOiI1MmNiMDYxZWI4ZGU5ZWNmNTNmZjExNTRmYWVkMTE2NDU0YTRhN2RhY2Y5NTlkZWU5ODg1YWNjMjBkNWRkMTJmIiwidGFnIjoiIn0%3D; path=/; secure; httponlyalphaeurekaselectnet_session=eyJpdiI6InhWQ2MydFJYbE02b014TGdUS2RSMEE9PSIsInZhbHVlIjoiSFNEN0ZmdDlzY2I0blp2WTQ0YytRcHpkdlA4YW9MVTUwbHdBSncySXJ4Qk5hOFhIOUZEVk9XQnZ" ] ]
        session_attributes
        0 of 0
        array:5 [ "_token" => "DQx0rJiXra95UXuQn77Nvq88XgAkKCN4WW5p8RKd" "uc_cart_id" => "f1d1a25252c4cb0a1883ef9f872cf3bb" "_previous" => array:1 [ "url" => "https://alpha.eurekaselect.com/chapter/2270" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-17 23:29:29GET/chapter/2270112192