康 · 祝贺 | Pharmaron Holds Tenth Annual Symposium

2023-09-26

临床研究

Pharmaron Holds Tenth Annual Symposium on Synthetic and Medicinal ChemistryPharmaron held its 10th Symposium on Synthetic and Medicinal Chemistry. After being postponed for three years due to the pandemic, the symposium came back with high expectations. This symposium offers an opportunity for our scientists and partners to learn from world-class industry and academic researchers that presented the latest advancements in synthetic and medicinal chemistry. The goal of this symposium is to spark innovation, as that is the foundation of Pharmaron's learning culture and building block for continued success.Group Picture of SpeakersProf. Matthew Gaunt from University of Cambridge presented on the development of visible-light mediated carbonyl alkylative amination (CAA) and carbonyl acylative amination (CAcylA) strategy demonstrated by the synthesis of complex tertiary amines and α-amino carbonyl compounds, via addition of in situ generated alkyl radicals and acyl radicals on iminium ions. This is difficult to achieve by current chemistry. In addition, Prof. Gaunt described how his group developed a high-throughput experimentation platform that accelerates the implementation of novel transformations and predictive modeling. Prof Gaunt’s team has successfully developed methods of C-8 amination of guanosine base in nucleic acids selectively via photo induced activation of n-π EDA (electron donor-acceptor) complex to form ammonium radical cation.Dr. Wei Zhu from China Innovation Center of Roche presented the discovery and development of core protein allosteric modulator Linvencorvir (RG7907) for the treatment of chronic HBV infections. The development of an earlier candidate compound met with a challenge associated with strong CYP3A4 induction in clinic. Through a rational structure-activity-relationship campaign aided by CADD and structural biology, which dialed out CYP3A4 induction while maintaining desired anti-HBV activity, the second generation CpAM RG7907 was discovered with favorable pharmacokinetics, pharmacodynamics and safety profiles in animals, supporting its clinical development. The early clinical data in PK, tolerability and efficacy warrants its value for further clinical development.Dr. Mingxiang Lin from Analytical R&D, MSD, introduced the application of a novel 2D-prep-HPLC platform, which was developed by Pharmaron. The aim was to overcome the unmet challenges in impurity isolation and purification, and achieve direct isolation of target impurities in quantities ranging from milligrams to grams. With development and improvement, this platform could play an important role in various fields of pharmaceutical R&D.Dr. Steven. F. Oliver from Johnson & Johnson introduced the application of new technologies in process chemistry. By initially using a webcam, he and his team could “see” what has been going on in a reaction flask and then went beyond that by designing new technologies that are of non-invasive analysis with multiple parameters in parallel in a real time. One such example of the application of artificial intelligence and digital technologies in process development is demonstrated with improved efficiency of the solvent process, saving more than 30% of cost and time. Another example using this approach involved the particle size optimization of hydraulic centrifugal separation technology that enabled better particle size control than traditional crystallization. Dr. Oliver also touched upon its application in self-optimization process for CMC.Dr. Louis-Charles Campeau of MSD discussed one of MSD’s strategies to “change the world through one reaction at a time” approach by giving an example of the development of a macrocyclic peptide molecule MK-0616, which shows the typical merits from both small molecule and biologics worlds, e.g., orally available while with antibody-like potency and selectivity. Starting from the original macrocyclic peptide molecule, the MSD team obtained the new macrocyclic peptide molecule MK-0616 through extensive structure-activity relationship studies. In addition, they optimized the synthetic route, from the original linear synthetic strategy that used solid phase peptide synthesis then the continuous cyclization to the convergent fragment-based synthetic strategy, which greatly reduced the synthetic steps of MK-0616. It is worth mentioning that Dr. Campeau and his team developed a new enzyme catalytic method that capitalizes on directed evolution for the synthesis of a key intermediate and its analogues, which greatly shortened the synthetic route and allowed for rapid SAR development.Prof. Peter Wipf from University of Pittsburgh presented his team’s innovative strategies in the total synthesis and systematic investigation of the CNS/GPCR effects of Ergot and Clavine Alkaloids. This seminal work brought us back to re-explore the traditional alkaloids with great medical potential in CNS disease area, through new chemistry and methodology development. Several novel classes of newly discovered alkaloids were discussed with improved CNS-target subtype selectivity, which could be translated into a better CNS safety profile. Moreover, the chemistry Prof. Wipf demonstrated allowed a rapid assembly of core structures (e.g., indole ring) with various functional groups attached which will benefit our research for the synthesis of indole-type and Ergot-type compounds.Mr. Tony Alorati from Pharmaron Hoddesdon Site in the UK, in a short session, reported that visible light photochemistry was established and embedded as a capability at Pharmaron Hoddesdon site. The capability of photochemistry screening platform and scale up model were demonstrated by an example of photo-induced decarboxylative fluorination with advantages of high yield and efficiency, with a scale of processing up to 1.5 kg material daily. Commercial scale design and build of photochemistry is ongoing through 2023/24. Hopefully, the strong photochemistry capability for API manufacturing could be ready for use in the not far distance future.Prof. Zhu-Jun Yao from Nanjing University introduced an oxonium intermediate his team discovered in the total synthesis of chlorofusin and was able to deliver it as air-stable isochromenylium salt. With thorough understanding of the characteristics of the unique chemical structure, Prof. Yao and the team developed a series of novel chemistry using this intermediate as the starting point. This approach was also expanded to enable an enantioselective cascade annulation, which eventually resulted in synthesis of the complicated multi ring fused chiral compounds. This phenomenal work allowed the synthesis of very complicated molecules in a very simple way, as demonstrated by successful synthesis of a few complex natural products efficiently.Prof. Tomislav Rovis from Columbia University introduced the latest progress on the red-shifting photoredox catalysis. He shared the new catalyst discovery and its synthetic applications for the construction of C-C bond and C-N bond by employing a strategy to red-shift popular blue light, which reduced the excitation energy by replacing Ru(II) complex with Os(II) or Ir(II) complexes, respectively. Based on the low energy and high selectivity characteristics of infrared light induced excitation, Prof. Rovis demonstrated this methodology’s value in protein labelling and opened a new channel to explore biology.更多精彩瞬间剪影（左右滑动可以查看更多）:左右滑动查看更多左右滑动查看更多左右滑动查看更多