Frontiers in Medicinal Chemistry

Volume: 1

The Contribution of Combinatorial Chemistry to Lead Generation: An Interim Analysis

Author(s): Anton E.P. Adang and Pedro H.H. Hermkens

Pp: 647-662 (16)

DOI: 10.2174/978160805204210401010647

* (Excluding Mailing and Handling)

Abstract

In the process of finding new drug candidates, medicinal chemists nowadays have a variety of options to choose from, one is to apply combinatorial chemistry techniques. Since the early 1990's synthetic and analytical methods as well as new technologies have been growing rapidly in the area of combinatorial chemistry. Applying these techniques has resulted in the production of large numbers of compounds. A trend is observed towards smaller libraries of compounds with more drug-like properties. An analysis is made to establish the contribution of combinatorial chemistry in providing new lead candidates for (pre-)clinical development towards new pharmaceutical products. Eleven representative examples are given to describe the impact of combinatorial chemistry on different levels of the lead discovery and optimization process. Furthermore, reports on combinatorial chemistry products that are already in (pre) clinical development were traced back to their source. The interim analysis showed only limited success of early combinatorial chemistry approaches in terms of delivering lead candidates. Second generation libraries appear to be more drug-like and focussed and may result in more compounds entering clinical development in the future.

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      • 13. app/Models/UserAccess/UserAccess.php:1266
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      • 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 <= 873421719 and j.to_ip >=873421719 )) and ((j.from_date <= 1739834392 and j.to_date >= 1739834392 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 2293) 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 <= 873421719 and j.to_ip >=873421719 )) and ((j.from_date <= 1739834392 and j.to_date >= 1739834392 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 2293) 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 <= 873421719 and j.to_ip >=873421719 )) and ((j.from_date <= 1739834392 and j.to_date >= 1739834392 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 2293)
      720μsalphaeurekaselec_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` <= 1739834392 and `b`.`banner_to_date` >= 1739834392 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.09msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: B
      • 2: 948
      • 3: 1739834392
      • 4: 1739834392
      • 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='b319c68e27c0aac9cea48f0705ec2aca'
      220μsalphaeurekaselec_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
        OxwkLJTEclL3eSCqpGo2xpDqxTuTj4kdmLrGCyVQ
        uc_cart_id
        b319c68e27c0aac9cea48f0705ec2aca
        _previous
        array:1 [ "url" => "https://alpha.eurekaselect.com/chapter/2293" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /chapter/2293
        status_code
        200
        
        status_text
        OK
        format
        html
        content_type
        text/html; charset=UTF-8
        request_query
        []
        
        request_request
        []
        
        request_headers
        0 of 0
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        request_cookies
        0 of 0
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        response_headers
        0 of 0
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        session_attributes
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        ClearShow all
        Date ↕MethodURLData
        #12025-02-17 23:19:52GET/chapter/2293112192