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Dive into the research topics where Martin Paul Edwards is active.

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Featured researches published by Martin Paul Edwards.


Journal of Medicinal Chemistry | 2011

Structure Based Drug Design of Crizotinib (Pf-02341066), a Potent and Selective Dual Inhibitor of Mesenchymal-Epithelial Transition Factor (C-met) Kinase and Anaplastic Lymphoma Kinase (Alk).

J. Jean Cui; Michelle Bich Tran-Dube; Hong Shen; Mitchell David Nambu; Pei-Pei Kung; Mason Alan Pairish; Lei Jia; Jerry Meng; Lee Andrew Funk; Iriny Botrous; Michele McTigue; Neil Grodsky; Kevin Ryan; Ellen Padrique; Gordon Alton; Sergei Timofeevski; Shinji Yamazaki; Qiuhua Li; Helen Y. Zou; James G. Christensen; Barbara Mroczkowski; Steve Bender; Robert Steven Kania; Martin Paul Edwards

Because of the critical roles of aberrant signaling in cancer, both c-MET and ALK receptor tyrosine kinases are attractive oncology targets for therapeutic intervention. The cocrystal structure of 3 (PHA-665752), bound to c-MET kinase domain, revealed a novel ATP site environment, which served as the target to guide parallel, multiattribute drug design. A novel 2-amino-5-aryl-3-benzyloxypyridine series was created to more effectively make the key interactions achieved with 3. In the novel series, the 2-aminopyridine core allowed a 3-benzyloxy group to reach into the same pocket as the 2,6-dichlorophenyl group of 3 via a more direct vector and thus with a better ligand efficiency (LE). Further optimization of the lead series generated the clinical candidate crizotinib (PF-02341066), which demonstrated potent in vitro and in vivo c-MET kinase and ALK inhibition, effective tumor growth inhibition, and good pharmaceutical properties.


Bioorganic & Medicinal Chemistry Letters | 2009

Rapid assessment of a novel series of selective CB2 agonists using parallel synthesis protocols: A Lipophilic Efficiency (LipE) analysis

Thomas Ryckmans; Martin Paul Edwards; Val A. Horne; Ana Monica Correia; Dafydd R. Owen; Lisa R. Thompson; Isabelle Tran; Michelle F. Tutt; Tim Young

A series of libraries were designed using the 1-(cyclopropylmethyl)-2-alkyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-5-ium templates 2a-b, and Sulfonamide derivatives 11a-n proved to be potent agonists of the CB(2) receptor. Analysis of the Lipophilic Efficiency (LipE) of potent compounds provided new insight for the design of potent, metabolically stable CB2 agonists.


Journal of Medicinal Chemistry | 2014

Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations.

Ted W. Johnson; Paul F. Richardson; Simon Bailey; Alexei Brooun; Benjamin J. Burke; Michael Raymond Collins; J. Jean Cui; Judith Gail Deal; Ya-Li Deng; Dac M. Dinh; Lars D. Engstrom; Mingying He; Jacqui Elizabeth Hoffman; Robert Louis Hoffman; Qinhua Huang; Robert Steven Kania; John Charles Kath; Hieu Lam; Justine L. Lam; Phuong Thi Quy Le; Laura Lingardo; Wei Liu; Michele McTigue; Cynthia Louise Palmer; Neal W. Sach; Tod Smeal; Graham L. Smith; Albert E. Stewart; Sergei Timofeevski; Huichun Zhu

Although crizotinib demonstrates robust efficacy in anaplastic lymphoma kinase (ALK)-positive non-small-cell lung carcinoma patients, progression during treatment eventually develops. Resistant patient samples revealed a variety of point mutations in the kinase domain of ALK, including the L1196M gatekeeper mutation. In addition, some patients progress due to cancer metastasis in the brain. Using structure-based drug design, lipophilic efficiency, and physical-property-based optimization, highly potent macrocyclic ALK inhibitors were prepared with good absorption, distribution, metabolism, and excretion (ADME), low propensity for p-glycoprotein 1-mediated efflux, and good passive permeability. These structurally unusual macrocyclic inhibitors were potent against wild-type ALK and clinically reported ALK kinase domain mutations. Significant synthetic challenges were overcome, utilizing novel transformations to enable the use of these macrocycles in drug discovery paradigms. This work led to the discovery of 8k (PF-06463922), combining broad-spectrum potency, central nervous system ADME, and a high degree of kinase selectivity.


Bioorganic & Medicinal Chemistry Letters | 2009

Using the Golden Triangle to optimize clearance and oral absorption

Ted W. Johnson; Klaus Ruprecht Dress; Martin Paul Edwards

The Golden Triangle is a visualization tool developed from in vitro permeability, in vitro clearance and computational data designed to aid medicinal chemists in achieving metabolically stable, permeable and potent drug candidates. Classifying compounds as permeable and stable and plotting molecular weight (MW) versus octanol:buffer (pH 7.4) distribution coefficients (logD) or estimated octanol:buffer (pH 7.4) distribution coefficients (elogD) reveals useful trends. Analysis of at least two orthogonal trends, such as permeability and clearance, can be extremely effective in balancing and optimizing multiple properties. In addition, molecular weight and logD impact potency-efficiency calculations, allowing potency, clearance and permeability to be optimized simultaneously.


Annual Reports in Medicinal Chemistry | 2010

Role of Physicochemical Properties and Ligand Lipophilicity Efficiency in Addressing Drug Safety Risks

Martin Paul Edwards; David A. Price

Publisher Summary This chapter focuses on the role of physiochemical properties and ligand lipophilicity efficiency in addressing drug safety risks. A significant challenge to drug discoverers and the pharmaceutical industry is to reduce the cost of exploring exciting new mechanisms of action and converting them into new medicines for the patient. Subsequently, adverse safety findings can have four fundamental origins and combinations: the primary pharmacology or mechanism of action of the compound under study; the secondary pharmacology of the compound under study; the presence of a well-defined structural fragment; and the overall physicochemical properties of the compound. The chapter summarizes recent developments regarding the role of physicochemical properties in safety liability and the emerging use of physicochemical property-based lead optimization using lipophilic ligand efficiency (LLE or LipE). It also illustrates the examples regarding the application of strategies based on increasing LLE or LipE and optimizing physicochemical properties as the key components of medicinal chemistry programs.


MedChemComm | 2010

Discovery of the highly potent PI3K/ mTOR dual inhibitor PF-04691502 through structure based drug design

Hengmiao Cheng; Shubha Bagrodia; Simon Bailey; Martin Paul Edwards; Jacqui Elizabeth Hoffman; Qiyue Hu; Robert Steven Kania; Daniel R. Knighton; Matthew A. Marx; Sacha Ninkovic; Shaoxian Sun; Eric Zhang

The phosphatidylinositol 3-kinase (PI3K) signaling pathway plays crucial roles in cell growth, proliferation and survival. Genomic aberrations in the PI3K pathway, such as mutational activation of PI3Kα or loss of function of tumor suppressor PTEN, have been closely linked to the development and progression of a wide range of cancers. Hence, inhibition of the key targets in the pathway, e.g. PI3K, AKT, mTOR, offers great potential for the treatment of cancer. Lead optimization through integration of structure based drug design (SBDD) and physical properties-based optimization (PPBO) led to the discovery of 2-amino-8-[trans-4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxypyridin-3-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (PF-04691502, 1) that demonstrated potent in vitro inhibitory activity against both PI3K and mTOR, excellent kinase selectivity, good ADMET, and robust in vivo efficacy in a mouse xenograft tumor growth model. Compound 1 is currently being evaluated in human clinical trials for the treatment of cancer.


Journal of Medicinal Chemistry | 2014

Design of Potent and Selective Inhibitors to Overcome Clinical Anaplastic Lymphoma Kinase Mutations Resistant to Crizotinib.

Qinhua Huang; Ted W. Johnson; Simon Bailey; Alexei Brooun; Kevin D. Bunker; Benjamin J. Burke; Michael Raymond Collins; Andrew Simon Cook; J. Jean Cui; Kevin Neil Dack; Judith Gail Deal; Ya-Li Deng; Dac M. Dinh; Lars D. Engstrom; Mingying He; Jacqui Elizabeth Hoffman; Robert Louis Hoffman; Patrick Stephen Johnson; Robert Steven Kania; Hieu Lam; Justine L. Lam; Phuong Thi Quy Le; Qiuhua Li; Laura Lingardo; Wei Liu; Melissa West Lu; Michele McTigue; Cynthia Louise Palmer; Paul F. Richardson; Neal W. Sach

Crizotinib (1), an anaplastic lymphoma kinase (ALK) receptor tyrosine kinase inhibitor approved by the U.S. Food and Drug Administration in 2011, is efficacious in ALK and ROS positive patients. Under pressure of crizotinib treatment, point mutations arise in the kinase domain of ALK, resulting in resistance and progressive disease. The successful application of both structure-based and lipophilic-efficiency-focused drug design resulted in aminopyridine 8e, which was potent across a broad panel of engineered ALK mutant cell lines and showed suitable preclinical pharmacokinetics and robust tumor growth inhibition in a crizotinib-resistant cell line (H3122-L1196M).


Bioorganic & Medicinal Chemistry Letters | 2009

N-(Pyridin-2-yl) arylsulfonamide inhibitors of 11β-hydroxysteroid dehydrogenase type 1: Discovery of PF-915275

Michael Siu; Theodore Otto Johnson; Yong Wang; Sajiv K. Nair; Wendy D. Taylor; Stephan James Cripps; Jean Matthews; Martin Paul Edwards; Thomas A. Pauly; Jacques Ermolieff; Arturo Castro; Natilie Hosea; Amy LaPaglia; Andrea Fanjul; Jennifer E. Vogel

N-(Pyridin-2-yl) arylsulfonamides are identified as inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1), an enzyme that catalyzes the reduction of the glucocorticoid cortisone to cortisol. Dysregulation of glucocorticoids has been implicated in the pathogenesis of diabetes and the metabolic syndrome. In this Letter, we present the development of an initial lead to an efficient ligand with improved physiochemical properties using a deletion strategy. This strategy allowed for further optimization of potency leading to the discovery of the clinical candidate PF-915275.


Journal of Medicinal Chemistry | 2012

Discovery of Pyrroloaminopyrazoles as Novel Pak Inhibitors.

Chuangxing Guo; Indrawan McAlpine; Junhu Zhang; Daniel D. Knighton; Susan Kephart; M. Catherine Johnson; Haitao Li; Djamal Bouzida; Anle Yang; Liming Dong; Joseph Timothy Marakovits; Jayashree Girish Tikhe; Paul G. Richardson; Lisa C. Guo; Robert Steven Kania; Martin Paul Edwards; Eugenia Kraynov; James G. Christensen; Joseph Piraino; Joseph H. Lee; Eleanor Dagostino; Christine Del-Carmen; Ya-Li Deng; Tod Smeal; Brion W. Murray

The P21-activated kinases (PAK) are emerging antitumor therapeutic targets. In this paper, we describe the discovery of potent PAK inhibitors guided by structure-based drug design. In addition, the efflux of the pyrrolopyrazole series was effectively reduced by applying multiple medicinal chemistry strategies, leading to a series of PAK inhibitors that are orally active in inhibiting tumor growth in vivo.


Bioorganic & Medicinal Chemistry Letters | 2010

The development and SAR of pyrrolidine carboxamide 11β-HSD1 inhibitors

Hengmiao Cheng; Jacqui Elizabeth Hoffman; Phuong T. Le; Sajiv K. Nair; Stephan James Cripps; Jean Matthews; Christopher Ronald Smith; Michele Yang; Stan Kupchinsky; Klaus Ruprecht Dress; Martin Paul Edwards; Bridget Mccarthy Cole; Evan Walters; Christine Loh; Jacques Ermolieff; Andrea Fanjul; Ganesh B. Bhat; Jocelyn Herrera; Tom Pauly; Natilie Hosea; Genevieve Paderes; Paul A. Rejto

The design and development of a series of highly selective pyrrolidine carboxamide 11beta-HSD1 inhibitors are described. These compounds including PF-877423 demonstrated potent in vitro activity against both human and mouse 11beta-HSD1 enzymes. In an in vivo assay, PF-877423 inhibited the conversion of cortisone to cortisol. Structure guided optimization effort yielded potent and stable 11beta-HSD1 selective inhibitor 42.

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