Discovery and SAR Study of Boronic Acid-Based Selective PDE3B Inhibitors from a Novel DNA-Encoded Library.

Human genetic evidence shows that PDE3B is associated with metabolic and dyslipidemia phenotypes. A number of PDE3 family selective inhibitors have been approved by the FDA for various indications; however, given the undesirable proarrhythmic effects in the heart, selectivity for PDE3B inhibition over closely related family members (such as PDE3A; 48% identity) is a critical consideration for development of PDE3B therapeutics. Selectivity for PDE3B over PDE3A may be achieved in a variety of ways, including properties intrinsic to the compound or tissue-selective targeting. The high (>95%) active site homology between PDE3A and B represents a massive obstacle for obtaining selectivity at the active site; however, utilization of libraries with high molecular diversity in high throughput screens may uncover selective chemical matter. Herein, we employed a DNA-encoded library screen to identify PDE3B-selective inhibitors and identified potent and selective boronic acid compounds bound at the active site.

Empowering Voices: Inspiring Women in Medicinal Chemistry.

As we celebrate International Women's Day 2024 with the theme "Inspire Inclusion", the women of the ACS Medicinal Chemistry Division (MEDI) want to foster a sense of belonging, relevance, and empowerment by sharing uplifting stories of what inspired them to become medicinal chemists. In this editorial, we are featuring female medicinal chemistry scientists to provide role models, encouragement, and inspiration to others. We asked women medicinal chemists to contribute a brief paragraph about what inspired them to become medicinal chemists or what inspires them today as medicinal chemists. The responses and contributions highlight their passions and motivations, such as their love of the sciences and their drive to improve human health by contributing to basic research and creating lifesaving drugs.

Empowering Voices: Inspiring Women in Medicinal Chemistry.

As we celebrate International Women's Day 2024 with the theme "Inspire Inclusion", the women of the ACS Medicinal Chemistry Division (MEDI) want to foster a sense of belonging, relevance, and empowerment by sharing uplifting stories of what inspired them to become medicinal chemists. In this editorial, we are featuring female medicinal chemistry scientists to provide role models, encouragement, and inspiration to others. We asked women medicinal chemists to contribute a brief paragraph about what inspired them to become medicinal chemists or what inspires them today as medicinal chemists. The responses and contributions highlight their passions and motivations, such as their love of the sciences and their drive to improve human health by contributing to basic research and creating lifesaving drugs.

Library Synthesis: Building Block Validation.

Completing a validation process to assess the reactivity of potential building blocks that can be included in a DNA-encoded library is important for ensuring the quality of a library. Here we describe the validation method used to assess the reactivity of potential building blocks to be included in a DNA-encoded library, with HATU acylation of carboxylic acid building blocks with an on-DNA amine substrate as an example.

Library Synthesis: Building Block Selection, Handling, and Tracking.

Careful selection and manipulation of small molecule building blocks is crucial to the success of a DNA-encoded library. Building block selection impacts the quality of the hits arising out of a selection assay, while proper sample handling and tracking ensure follow-up synthetic work is done with the appropriate synthetic map in mind. In this chapter, possible strategies for building block selection are outlined, as well as best practices for handling and tracking samples to be used for validation and library synthesis.

Engaging the Medicinal Chemists of Tomorrow.

The Young Medicinal Chemists Committee (YMCC) is a part of the larger ACS Division of Medicinal Chemistry (MEDI) and was formed to ensure that MEDI meets the needs of all medicinal chemists, including students and early career scientists. There is a clear need to offer additional, specific opportunities to this group of medicinal chemists within the MEDI division. Primary functions of YMCC include facilitating networking and mentorship opportunities, collaborating with international medicinal chemistry societies, and offering social programming for all MEDI members at ACS National Meetings. We are excited to continue to engage students and early career chemists through new initiatives and programming in the future. In this Editorial we highlight current initiatives relevant to early career medicinal chemists and solicit input from the larger medicinal chemistry community.