Quick Building Blocks (QBB): An Innovative and Efficient Business Model To Speed Medicinal Chemistry Analog Synthesis

Abstract

Many pharmaceutical companies have invested millions of dollars in establishing internal chemical stores to provide reliable access to large numbers of building blocks (BB) for the synthesis of new molecules, especially for the timely design and execution of parallel (library) synthesis. Recognizing budget and logistical limitations, we required a more economically scalable process to provide diverse BB. We disclose a novel business partnership that achieves the goals of just-in-time, economical access to commercial BB that increases chemical space coverage and accelerates the synthesis of new drug candidates. We believe that this model can be of benefit to companies of all sizes that are engaged in drug discovery by reducing cost, increasing diversity of analog molecules in a time-conscious manner, and reducing BB inventory. More efficient use of BB by customers may allow commercial vendors to devote a greater portion of their resources to preparing novel BB that increase chemical diversity as opposed to resynthesizing out-of-stock compounds that are inaccessible within company compound collections.

Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances

“…[19] In early 2000s, synthesis of building blocks became an important part of the industry, [20] and to date, many pharmaceutical companies have invested millions of dollars in establishing internal chemical stores of building blocks, and various business models were developed to ensure their accessibility. [21] Recently, AstraZeneca scientists proposed the key features of building blocks relevant to medicinal chemistry: the presence of a functional group with manageable chemical reactivity, as well as compliance of the fragment that is incorporated into the synthesized molecule with the so-called mnemonic 'Rule of 2'. [22] The latter cut-offs were proposed for the physico-chemical properties of the monofunctional building blocks: MW < 200, logP < 2, count of hydrogen bond donors HDon � 2, hydrogen bond acceptors HAcc � 4, rotatable bonds RotB � 4; balanced approach to sp 3 atom fraction favoring both saturated (Fsp 3 = 0.8…1) and mostly heteroaromatic (Fsp 3 = 0.2…0.5) compounds (Figure 1B).…”

Employing Photocatalysis for the Design and Preparation of DNA‐Encoded Libraries: A Case Study

“…In addition, we worked with HitGen to help us track these data and update our DEL database in a timely manner. To manage and track costs, we leveraged a model developed for our Quick Building Blocks (QBB) business model [97] . By implementing these modifications, cycle times have improved considerably.…”

Synthesis and functionalisation of a bifunctional normorphan 3D building block for medicinal chemistry

“…[6][7][8][9] Alongside this, there is now a recognition that the availability of 'high quality' building blocks is pivotal to the construction of compound screening collections that will deliver both good success rates in high-throughput screening and 'high quality' hits for development into potential drug candidates. [10][11][12] In this context, as part of AstraZeneca's 'strategic reagent initiative', Goldberg et al have parametrised building block quality in the form of a 'rule of 2' for key metrics: MW < 200, clogP < 2, hydrogen bond donor count (HBD) £ 2 and hydrogen bond acceptor count (HBA) £ 4. 10 building blocks that are equipped with cross-coupling potential -this is a key design feature of 3D building block 1.…”