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«Synthesis and structure-activity relationship of liposomal substrates for phospholipase A(2) Viart, Helene Marie-France; Clausen, Mads Hartvig ...»

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Synthesis and structure-activity relationship of liposomal substrates for

phospholipase A(2)

Viart, Helene Marie-France; Clausen, Mads Hartvig

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Viart, H. M-F., & Clausen, M. H. (2011). Synthesis and structure-activity relationship of liposomal substrates for phospholipase A(2). ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 242, MEDI 344.

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American Chemical Society Division of Medicinal Chemistry 242nd ACS National Meeting, Denver, CO, August 28 - September 1, 2011 J. Barrish, Program Chair


General Oral Session J. Barrish, Organizer; D. Hertzog, Presiding Papers 1-10 siRNA S. Barrett, Organizer; M. Cameron, Organizer; M. Cameron, Presiding; S. Barrett, Presiding Papers 11-14


General Oral Session J. Barrish, Organizer; K. Seley-Radtke, Presiding Papers 15-25 First Time Disclosure of Clinical Candidate A. J. Robichaud, Organizer; A. J. Robichaud, Presiding Papers 26-30


General Poster Session J. Barrish, Organizer Papers 31-157


Making a Large Impact Through Medicinal Chemistry on Proteins: Methods, Applications to Drug Discovery, and Recent Clinical Results T. Pillow, Organizer; T. Pillow, Presiding Papers 158-163 Innovation in the 21st Century: The Evolution of Drug Discovery D. Beshore, Organizer; D. Beshore, Presiding Papers 164-170


E. B. Hershberg Award for Important Discoveries in Medicinally Active Substances: Symposium in Honor of Richard B. Silverman J. Barrish, Organizer; J. Zablocki, Presiding Papers 171-175 A Medicinal Chemist's Toolbox: Taking Inventory P. Scola, Organizer; N. Meanwell, Organizer; N. Meanwell, Presiding; P. Scola, Presiding Papers 176-180 Antithrombotic Therapy S. Chackalamannil, Organizer; S. Chackalamannil, Presiding Papers 181-186


Sci-Mix J. Barrish, Organizer; J. Barrish, Presiding Papers 31, 375, 45, 347, 33, 376, 339, 134, 147, 118, 98, 50, 380, 96, 127, 102, 279, 48, 346, 122, 293, 243, 288, 136, 330, 284, 289, 260, 320, 95, 379, 264, 267, 271, 306, 343, 250, 274


General Oral Session J. Barrish, Organizer; J. Barrish, Presiding Papers 187-193 MEDI Awards Symposium J. Zablocki, Organizer; L. Hurley, Organizer; J. Zablocki, Presiding; P. Woster, Presiding Papers 194-201


Tissue Selective Therapeutic Agents A. Gilbert, Organizer; B. Raymer, Organizer; P. T. Cheng, Organizer; A. Gilbert, Presiding; B. Raymer, Presiding; P. T. Cheng, Presiding Papers 202-206 GPCR PAMs, NAMs and SAMs: A New Way to Affect GPCR Receptors J. Macor, Organizer; J. Macor, Presiding Papers 207-212


Drug Discovery Research Centers G. Georg, Organizer; W. Moos, Organizer; G. Georg, Presiding; W. Moos, Presiding Papers 213-217 Targeting Tumor Stem Cells W. Priebe, Organizer; S. Peluso, Organizer; S. Peluso, Presiding; W. Priebe, Presiding Papers 218-222


Exploiting the Metabolic Differences between Normal and Cancer Cells F. Salituro, Organizer; T. Bannister, Organizer; F. Salituro, Presiding; T. Bannister, Presiding Papers 228-235 Drug Discovery Research Centers G. Georg, Organizer; W. Moos, Organizer; G. Georg, Presiding; W. Moos, Presiding Papers 223-227 Huntington's Disease: Recent Advances in Disease Diagnosis and Potential Disease Modifying Therapeutics C. Dominguez, Organizer; C. Dominguez, Presiding; M. Maillard, Presiding Papers 236WEDNESDAY EVENING General Poster Session J. Barrish, Organizer Papers 242-369


General Oral Session J. Barrish, Organizer; J. Barrish, Presiding; P. T. Cheng, Presiding Papers 370-380 From Paper to PK Profile without Synthesis: Everything a Medicinal Chemist Needs to Know About Predictive DMPK J. Kenny, Organizer; J. Kenny, Presiding Papers 381-385 MEDI 1 WITHDRAWN MEDI 2 Discovery of phosphodiesterase-10 (PDE10) inhibitors for the treatment of schizophrenia Izzat T Raheem1, izzat_raheem@merck.com; Jim Barrow2; Rodney A Bednar3; Michael J Breslin1; Joseph Bruno3; Victoria Cofre3; Paul J Coleman1; Christine Fandozzi4; Joy Fuerst5; Lisa Gold6; Nicole Hill5; Pete H Hutson6; Sarah Huszar7; Monika Kandebo6;

Amanda Kemmerer3; Somang H Kim4; Raghu Krishnan3; Wei Lemaire3; Bennett Ma4;

Georgia McGaughey8; Sanjeev Munshi9; Shannon Nguyen7; Sophie ParmentierBatteur6; John D Schreier1; Sujata Sharma9; William D Shipe2; Sean Smith6; Jason Uslaner7; Youwei Yan9; Christopher D Cox1. (1) Program Team Chemistry, Merck & Co., Inc., West Point PA 19486, United States (2) Automated Synthesis and Purification, Merck & Co., Inc., West Point PA 19486, United States (3) In Vitro Sciences, Merck & Co., Inc., West Point PA 19486, United States (4) Drug Metabolism, Merck & Co., Inc., West Point PA 19486, United States (5) Basic Pharmaceutical Sciences, Merck & Co., Inc., West Point PA 19486, United States (6) Neurosymptomatics, Merck & Co., Inc., West Point PA 19486, United States (7) In Vivo Pharmacology, Merck & Co., Inc., West Point PA 19486, United States (8) Chemistry Modeling and Informatics, Merck & Co., Inc., West Point PA 19486, United States (9) Structural Chemistry, Merck & Co., Inc., West Point PA 19486, United States Schizophrenia is a chronic and debilitating neurological disease with onset typically occurring during early adulthood. The disease is characterized by a combination of positive (hallucinations), negative (anhedonia, social withdrawal), and cognitive symptoms, and is estimated to affect 1% of the global population. While currently marketed "typical" and "atypical" therapeutics exist, they are prone to an array of adverse events (AEs), often resulting in discontinuation due to poor efficacy and/or tolerability. As such, alternative pharmacological approaches toward treating schizophrenia represent an unmet medical need. The phosphodiestereases (PDEs) are a superfamily of 11 enzymes responsible for the hydrolytic degradation of the second messengers cAMP and cGMP. Specifically, PDE10 is highly expressed and localized in the mammalian striatum, and is implicated in the regulation of cyclic nucleotide signalling cascades that intersect both the glutamatergic and dopaminergic pathways regulating behavioral control. As such, inhibition of PDE10 is hypothesized to represent a mechanistically novel approach toward the treatment of schizophrenia, and recent preclinical results support this hypothesis. We describe the discovery and development of potent and orally bioavailable tetrahydropyridopyrimidine inhibitors of PDE10 obtained by systematic optimization of a proprietary Merck HTS lead. Leading compounds exhibit sub-nanomolar potencies, excellent pharmacokinetic (PK) properties, and clean off-target profiles. These inhibitors display in vivo target engagement as measured by both an ex vivo occupancy assay and increased striatal cGMP levels upon oral dosing. They also display dose-dependent efficacy in key pharmacodynamic (PD) assays predictive of anti-psychotic activity, including the psychostimulant-induced rat hyperlocomotion assay and the conditioned avoidance response assay.

MEDI 3 Discovery of JNJ-42601572, a γ-secretase modulator with potent, central activity in mouse and dog Francois Bischoff, fbischof@its.jnj.com; Harrie Gijsen, hgijsen@its.jnj.com; Didier Berthelot; Michel De Cleyn; Gregor Macdonald; Daniel Oehlrich; Michel Surkyn; Andres Trabanco; Gary Tresadern; Sven Van Brandt; Adriana I Velter; Herman Borghys;

Chantal Masungi; Marc Mercken. Department of Neuroscience, Janssen Research & Development, Beerse B-2340, Belgium Accumulation of neurotoxic amyloid-beta 42 peptides (Ab42) in the brain is a hallmark of Alzheimer's disease (AD). Gamma-secretase, an intramembrane-cleaving protease responsible for the production of amyloid-beta peptides, has emerged as an important target for the development of novel therapeutics for AD. γ-Secretase modulation rather than plain inhibition has been postulated to be an alternative strategy to intervene pharmacologically within the amyloid cascade. It causes a product shift at the expense of Ab42 to the shorter, more soluble and less amyloidogenic Ab38 without inhibiting NOTCH proteolytic processing. The design and the synthesis of several chemical subclasses of in vitro and in vivo potent γ-secretase modulators (GSM) will be presented as well as their drug-like properties. This study has led to the identification of our lead compound, JNJ-42601572 which, in a non-transgenic mouse brain, upon oral dosing (30 mg/kg, 4 h) induces a 63% lowering of Ab42 levels and a 91% increase of Ab38 levels with unchanged total levels of amyloid peptides. Moreover, JNJ-42601572 elicits very potent in vivo activity across species as it induces upon oral dosing (20 mg/kg, 8 h) a 60% lowering of Ab42 levels and a 60% increase of Ab38 levels in dog cerebrospinal fluid.

MEDI 4 Discovery of a series of brain-penetrant kynurenine aminotransferase II inhibitors for the treatment of schizophrenia Amy B. Dounay, amy.dounay@pfizer.com. Neuroscience Medicinal Chemistry, Pfizer Worldwide Research and Development, Groton CT 06340, United States Kynurenine aminotransferase (KAT) II has been identified as a potential new target for treatment of cognitive impairment associated with schizophrenia. Following a high throughput screen, cyclic hydroxamic acid PF-04859989 emerged as a lead compound for the program. PF-04859989 represents the first reported brain penetrant tool compound for KATII. Additionally, our studies revealed that PF-04859989 inhibits KATII irreversibly by forming a covalent adduct with co-factor pyridoxal phosphate (PLP) in the enzyme active site. Key challenges for the medicinal chemistry team included developing a clear understanding of the structural features affecting the irreversibility of inhibition and design of compounds with potency at both rat and human KATII isozymes. X-ray crystallography, homology modeling, and biophysical studies to probe irreversibility have been critical components of the team's design strategy. Additionally, protein NMR experiments with 13C-labeled PF-04859989 have provided deeper insight into the mechanism of irreversible inhibition. Highlights of these studies and their impact on the team's lead optimization efforts will be described.

MEDI 5 Design and synthesis of Benzimidazole based inhibitors of Raf kinase: A med.

Chem approach towards the discovery of Phase II clinical candidate RAF265 Savithri Ramurthy1, savithri.ramurthy@novartis.com; Payman Amiri2; Abran Costales1;

Johanna M Jansen1; Barry Levine3; Sylvia Ma2; Christopher M McBride3; Teresa Pick4;

Daniel J. Poon1; Cynthia M. Shafer1; Darrin Stuart2; Leonard Sung3; Ahmad Hashash5;

Paul Renhowe1; Eleni Venetsanakos2; Jeremy Murray3; Brent Appleton1; Mina Aikawa2;

Joelle Verhagen3; Kimberly Aarderlin2. (1) Global Discovery chemistry / Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research, Emeryville CA 94608, United States (2) Oncolgy, Novartis Institutes for Biomedical Research, Emeryville CA 94608, United States (3) NA, United States (4) Lawrence Livermore Laboratories, United States (5) Gilead Sciences, United States The Ras/Raf/MEK/ERK pathway plays a central role in mediating proliferation and survival signals from the cell membrane to the nucleus and cytoplasm. Activation of this pathway often occurs in cancer cells, the importance of which is underscored by the observation that activating mutations in Ras and B-Raf frequently occur in human cancer. Thus a potent Raf inhibitor could have a significant impact in treating cancers that are dependent on activated Ras or Raf for survival and proliferation signaling.

Malignant melanoma represents a promising indication for a Raf inhibitor given the high percentage of B-Raf (60-70%) mutations and the huge unmet medical need. Here, we describe the medicinal chemistry approaches which led to the discovery of Raf265, a novel, orally bioavailable small molecule inhibitor of c-Raf, B-Raf and mutant B-Raf (V600E) that also inhibits VEGFR-2. This target profile provides two potential mechanisms for inhibiting tumor growth: direct anti-proliferative/pro-apoptotic effects on tumor cells through inhibition of Raf, and anti-angiogenic activity through inhibition of VEGFR-2. Design strategy, synthesis and the in vitro, in vivo activities of the early Benzimidazole analogs and Raf 265 will also be discussed.


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