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Tim JONCKERS 2ND ALPINE WINTER CONFERENCE ON MEDICINAL AND SYNTHETIC CHEMISTRYTim ST. ANTON, AUSTRIA | JONCKERS JANUARY 19 – 23, 2020 JANSSENwww.alpinewinterconference.org PHARMACEUTICA Prof. Erick BOOK OF ABSTRACTS SCIENTIFIC ORGANISING COMMITTEE Klemens HOEGENAUER (Novartis Institutes for BioMedical Research, Switzerland) Karl Heinz KRAWINKLER (Novartis Institutes for BioMedical Research, Switzerland) Antonia F. STEPAN (F. Hoffmann-La Roche, Switzerland) 1 ALPINE20-BookAbstracts-Covers.indd 1 20/12/19 17:18 CONTENT SPEAKERS & ORAL COMMUNICATIONS - Biographies and Abstracts 3 POSTERS - Frontiers of Synthetic Chemistry 73 POSTERS - Structure and Biophysics - Companions for Medicinal Chemistry 89 POSTERS - Protein Degradation: New Rules for Drug Discovery 93 POSTERS - Innovation and Inspiration from Natural Products 95 POSTERS - Accelerating Drug Discovery by Intelligence Augmentation 107 POSTERS - Drug Discovery Tales 113 POSTERS - Others 133 LIST OF ABSTRACTS 143 LIST OF AUTHORS 149 LIST OF PARTICIPANTS 155 2 SPEAKERS & ORAL COMMUNICATIONS Biographies and Abstracts 3 Sarah E. REISMAN California Institute of Technology, United States arah E. Reisman earned a BA in Chemistry from Connecticut College in 2001, and her Ph.D. in Schemistry from Yale University in 2006, under the direction of Prof. John L. Wood. From 2006– 2008, Sarah worked as an NIH fellow with Prof. Eric Jacobsen at Harvard University, and then joined the faculty at the California Institute of Technology where she is now a Professor of Chemistry and a Heritage Medical Research Institute Investigator. er laboratory seeks to discover, develop, and study new chemical reactions within the Hcontext of natural product total synthesis. 4 KL01 NECESSITY IS THE MOTHER OF INVENTION: NATURAL PRODUCTS AND THE CHEMISTRY THEY INSPIRE Sarah E. Reisman California Institute of Technology, Division of Chemistry and Chemical Engineering, 1200 E. California Blvd, MC 101-20, Pasadena CA 91125, [email protected] The chemical synthesis of natural products provides an exciting platform from which to conduct fundamental research in chemistry and biology. Our group is currently pursuing the synthesis of a number of structurally complex natural products, including the diterpenoids perseanol and talatisamine. The densely-packed arrays of heteroatoms and stereogenic centers that constitute these polycyclic targets challenge the limits of current technology and inspire the development of new synthetic strategies and tactics. This seminar will describe the latest progress in our methodological and target-directed synthesis endeavors. 5 Li DI Pfizer, United States r Li Di has over 25 years of experience in the pharmaceutical industry including Pfizer, DWyeth and Syntex. She is currently a research fellow at Pfizer, Groton, CT. er research interests include the areas of drug metabolism, pharmacokinetics, drug-drug Hinteractions, absorption, transporters, and blood–brain barrier. he has over 145 publications including two Sbooks and presented over 85 invited lectures. he is a recipient of the Thomas Alva Edison Patent Award, the New Jersey Association for SBiomedical Research Outstanding Woman in Science Award, the Wyeth President’s Award and Peer Award for Excellence. 6 PL01 STRUCTURAL ATTRIBUTES INFLUENCING UNBOUND TISSUE DISTRIBUTION Li Di Pfizer Worldwide Research and Development, 280 Shennecossett Rd, CT 06340 Groton, United States Free drug concentrations in the tissues are essential to develop pharmacokinetic / pharmacodynamic relationships, estimate therapeutic index, and predict dose for disease targets residing in tissues. Unbound tissue-to-plasma partition coefficient (Kpuu) is a useful parameter to understand asymmetry tissue distribution and guide structural modification to enhance or restrict tissue exposure. As the literature information on tissue K puu is scarce and human data is difficult to obtain, rat in vivo tissue Kpuu data of 56 structurally diverse compounds were generated in white adipose, brain, heart, liver, and skeletal muscle. Selective tissue distribution was observed for certain compounds, demonstrating the feasibility of targeting or restricting drug exposure in certain tissues through rational drug design. Structural attributes governing Kpuu in each tissue were identified, such as: (1) Compounds with high TPSA and hydrogen binding capacity tend to be impaired in the brain; (2) Strong acids tend to be restricted for muscle penetration, while compounds with high passive permeability tend not to be impaired in the muscle; (3) Large lipophilic acids tend to be enriched in the liver, potentially due to active uptake by OATPs; and (4) Compounds with low lipophilicity tend to be impaired in the adipose. The rank ordering of the median tissue Kpuu values was: liver (4.5) > heart (1.8) > adipose (1.2) > skeletal muscle (0.6) > brain (0.05), with liver being most enriched and brain most impaired. Multiple mechanisms can impact Kpuu including passive permeability, uptake and efflux transport, metabolism and tissue bulk flow. The structural attributes identified provide valuable insights on design principles for asymmetric tissue distribution to improve efficacy or reduce toxicity. 7 Martin HAYES AstraZeneca, Sweden artin Hayes is currently Biocatalysis Leader in Hit Discovery, part of Discovery Sciences Mat AstraZeneca in Gothenburg, Sweden. He has over 25 years of industrial experience in drug discovery and development in large pharma and biotech with research interests in biocatalysis, biotransformation, natural products chemistry, analytical chemistry, structure elucidation and drug design. MH has held roles as a Team Leader, Design Leader and Project Leader at AstraZeneca, GlaxoSmithKline and Xenova. He led preclinical biotransformation studies on the P2Y12 blockbuster Brilinta/Brilique and DMPK design efforts for the FLAP inhibitor AZD5718 for atherosclerosis, currently in Phase 2. He is Industrial Lead for small molecule development and member of the Prosperity Partnership Management Board for the EPSRC/ BBRSC PP Grant to establish a new Centre for Biocatalytic Manufacture of New Modalities (CBNM) at Manchester University (2018-2023). He was PI on the Marie Curie FP7 funded P4FIFTY project (2013- 2017). e has published over 35 papers in peer- reviewed journals, holds 14 patents and was Hmade a Fellow of the Royal Society of Chemistry in 2000. Martin worked with Prof Tom Simpson FRS at the University of Bristol on mechanistic aspects of fungal polyketide chain assembly, followed by a postdoctoral fellowship with Prof Bryan Jones at University of Toronto. 8 PL02 METABOLISM OF STRAINED RINGS: TALES OF THE UNEXPECTED Martin Hayes Hit Discovery, Discovery Sciences , Biopharmaceuticals R&D, AstraZeneca, Gothenburg Strained rings and in particular combinations of strained spiro-ring systems are commonly used motifs used in drug discovery in lead generation and optimization programmes. Often ring systems of this type are utilized to modulate physicochemical properties e.g. solubility, pKa and/or DMPK properties such as in vitro metabolic stability (Clint) or permeability (P-app). Recent work from our group has highlighted the unexpected importance of the long-studied enzyme microsomal epoxide hydrolase in the in vitro clearance of simple and spiro-oxetane rings to form diol metabolites. This metabolic pathway has been demonstrated on two distinct structural series from in-house lead optimization programmes. An homology model based on the mEH crystal structure from Bombyx mori was used in attempts to rationalize substrate binding. It may be possible to use oxetane-based design elements to reduce dependency on CYP mediated clearance. Further studies on spiro oxetanyl-azetidines have revealed the importance of soluble glutathione transferases in the clearance of the MCHr1 antagonist AZD1979. Human recombinant GSTs including GST A1, A2-2, M1a, M2-2, T1-1 all catalyzed the formation of ring opened metabolites. Interestingly MetID studies using a combination of HRMS and NMR revealed ring opening in the spiro oxetanyl-azetidine containing AZD1979 took place on the azetidine, leaving an intact oxetane. Various downstream oxetane containing metabolites from GS-conjugate processing were also characterized. Compounds in this series show no GSH conjugation in regular HLM catalyzed GSH ‘trapping’ assays. In-house database searching indicated this metabolic pathway operating on simple azetidines. 9 Falgun SHAH Merck Sharp & Dohme, United States r Falgun is currently an Associate principal scientist and computational ADME & toxicology Ddomain lead within the discovery chemistry group at Merck, West Point. is interest lies in applying machine learning and data mining approaches to identify Hpotential ADME and safety liabilities within chemotypes. is current role involves influencing medicinal chemistry project teams to utilize in silico HADMET approaches during post-HTS work- up to enable them to bring high-quality chemical series forward. Prior to Merck, Falgun worked in compound safety prediction group at Pfizer for 4.5 years where he deployed in silico and informatics approaches to identify new mechanisms of organ toxicities in particularly drug-induced liver injury and cardiotoxicity. He has over 25 publications in peer- reviewed journals and multiple invited presentations. Falgun is trained as a pharmacist and holds a Ph.D. in medicinal/computational chemistry. 10 PL03 LEVERAGING IN SILICO ADMET PROFILES AND ANCILLARY PHARMACOLOGY TO INFLUENCE PRIORITIZATION OF HIT SERIES WITH HIGHER PROBABILITY
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