Fragment Based Lead Generation has traditionally been focused on fully structure enabled campaigns with the aim of generating novel lead series. However, there are many other less resource intensive ways to use fragment information to guide chemistry efforts in drug discovery projects. Fragment information can be used to: in synergy with HTS to arrive at the most promising hit series; in fragmenting hits and leads in order to better understand their SAR; to address issues such as metabolic stability; in experimentally based scaffold hopping in order to rapidly develop new lead series. Here we present examples of these approaches in the discovery of inhibitors for inducible nitric oxide synthase (iNOS).<br/><br/>iNOS has long been considered to be a promising anti-inflammatory and pain drug target. The protein has a highly ligandable binding pocket, i.e. finding potent ligands has been relatively straight forward. However, even for such tractable targets fragments can offer important contributions. We have used fragment information in synergy with HTS outputs in order to identify the most promising hit series. In addition, fragment structure-activity relationships helped deduce the binding mode for a pyridooxazole hit series that proved surprisingly difficult to optimize. Fragment screening was used to identify the most potent and promising variants of a quinazoline scaffold. This information was then used to address intellectual property challenges for this quinazoline series. For a benzoxazolone series, fragment screening was used to address metabolic stability issues. A series of fragment analogs were analyzed to identify potential changes to the core scaffold, prior to investing in complex chemistry synthesis of full-length ligands. Finally, two fully fragment derived lead series were developed in record time using experimentally based scaffold hopping and structure-based drug design. These two series, based on a uracil and a phthalazinone fragment hit, were developed to give compounds with low nM cellular IC50s and lead-like properties.

Improved inhibitors of inducible nitric oxide synthase (iNOS) through fragment assisted lead generation and optimization

249th National Meeting (2015)

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