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John E Tellew,
Marion Lanier,
Manisha Moorjani,
Emily Lin,
Zhiyong Luo, Deborah H Slee,
Xiaohu Zhang,
Sam R J Hoare,
Dimitri E Grigoriadis,
Yves St Denis,
Romano Di Fabio,
Enza Di Modugno,
John Saunders,
John P Williams
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ABSTRACT: Antagonists of the corticotropin-releasing factor (CRF) neuropeptide may prove effective in treating stress and anxiety related disorders. In an effort to identify antagonists with improved physico-chemical properties a new series of CRF(1) antagonists were designed to substitute the propyl groups at the C7 position of the pyrazolo[1,5-a]pyrimidine core of 1 with heterocycles. Compound (S)-8d was identified as a high affinity ligand with a pK(i) value of 8.2 and a functional CRF(1) antagonist with pIC(50) value of 7.0 in the in vitro CRF ACTH production assay.
Bioorganic & medicinal chemistry letters 10/2010; 20(24):7259-64. · 2.65 Impact Factor
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Marion C Lanier,
Manisha Moorjani,
Zhiyong Luo,
Yongsheng Chen,
Emily Lin,
John E Tellew,
Xiaohu Zhang,
John P Williams,
Raymond S Gross,
Sandra M Lechner, [......],
Marilyn Zhao,
Robert Petroski,
María I Crespo,
José-Luis Díaz,
John Saunders,
Jenny Wen,
Zhihong O'Brien,
Kayvon Jalali,
Ajay Madan, Deborah H Slee
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ABSTRACT: In the present article, we report on a strategy to improve the physical properties of a series of small molecule human adenosine 2A (hA2A) antagonists. One of the aromatic rings typical of this series of antagonists is replaced with a series of aliphatic groups, with the aim of disrupting crystal packing of the molecule to lower the melting point and in turn to improve the solubility. Herein, we describe the SAR of a new series of water-soluble 2,4,6-trisubstituted pyrimidines where R1 is an aromatic heterocycle, R2 is a short-chain alkyl amide, and the typical R3 aromatic heterocyclic substituent is replaced with an aliphatic amino substituent. This approach significantly enhanced aqueous solubility and lowered the log P of the system to provide molecules without significant hERG or CYP liabilities and robust in vivo efficacy.
Journal of Medicinal Chemistry 02/2009; 52(3):709-17. · 4.80 Impact Factor
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ABSTRACT: Beginning with the discovery of the structure of deoxyribose nucleic acid in 1953, by James Watson and Francis Crick, the sequencing of the entire human genome some 50 years later, has begun to quantify the classes and types of proteins that may have relevance to human disease with the promise of rapidly identifying compounds that can modulate these proteins so as to have a beneficial and therapeutic outcome. This so called 'drugable space' involves a variety of membrane-bound proteins including the superfamily of G-protein-coupled receptors (GPCRs), ion channels, and transporters among others. The recent number of novel therapeutics targeting membrane-bound extracellular proteins that have reached the market in the past 20 years however pales in magnitude when compared, during the same timeframe, to the advancements made in the technologies available to aid in the discovery of these novel therapeutics. This review will consider select examples of extracellular drugable targets and focus on the GPCRs and ion channels highlighting the corticotropin releasing factor (CRF) type 1 and gamma-aminobutyric acid receptors, and the Ca(V)2.2 voltage-gated ion channel. These examples will elaborate current technological advancements in drug discovery and provide a prospective framework for future drug development.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 10/2008; 34(1):106-25. · 6.99 Impact Factor
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Manisha Moorjani,
Zhiyong Luo,
Emily Lin,
Binh G Vong,
Yongsheng Chen,
Xiaohu Zhang,
Jaimie K Rueter,
Raymond S Gross,
Marion C Lanier,
John E Tellew,
John P Williams,
Sandra M Lechner,
Siobhan Malany,
Mark Santos,
María I Crespo,
José-Luis Díaz,
John Saunders, Deborah H Slee
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ABSTRACT: In this report, the strategy and outcome of expanding SAR exploration to improve solubility and metabolic stability are discussed. Compound 35 exhibited excellent potency, selectivity over A(1) and improved solubility of >4 mg/mL at pH 8.0. In addition, compound 35 had good metabolic stability with a scaled intrinsic clearance of 3 mL/min/kg (HLM) and demonstrated efficacy in the haloperidol induced catalepsy model.
Bioorganic & medicinal chemistry letters 09/2008; 18(20):5402-5. · 2.65 Impact Factor
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Xiaohu Zhang,
Jaimie K Rueter,
Yongsheng Chen,
Manisha Moorjani,
Marion C Lanier,
Emily Lin,
Raymond S Gross,
John E Tellew,
John P Williams,
Sandra M Lechner, [......],
Tanya Joswig,
Siobhan Malany,
Mark Santos,
Julio C Castro-Palomino,
María I Crespo,
Maria Prat,
Silvia Gual,
José-Luis Díaz,
John Saunders, Deborah H Slee
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ABSTRACT: A series of N-pyrimidinyl-2-phenoxyacetamide adenosine A(2A) antagonists is described. SAR studies led to compound 14 with excellent potency (K(i) = 0.4 nM), selectivity (A(1)/A(2A) > 100), and efficacy (MED 10 mg/kg p.o.) in the rat haloperidol-induced catalepsy model for Parkinson's disease.
Bioorganic & medicinal chemistry letters 04/2008; 18(6):1778-83. · 2.65 Impact Factor
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Deborah H Slee,
Yongsheng Chen,
Xiaohu Zhang,
Manisha Moorjani,
Marion C Lanier,
Emily Lin,
Jaimie K Rueter,
John P Williams,
Sandra M Lechner,
Stacy Markison, [......],
Kayvon Jalali,
Yang Sai,
Zhiyang Zuo,
Chun Yang,
Julio C Castro-Palomino,
María I Crespo,
Maria Prat,
Silvia Gual,
José-Luis Díaz,
John Saunders
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ABSTRACT: Previously we have described a novel series of potent and selective A 2A receptor antagonists (e.g., 1) with excellent aqueous solubility. While these compounds are efficacious A 2A antagonists in vivo, the presence of an unsubstituted furyl moiety was a cause of some concern. In order to avoid the potential metabolic liabilities that could arise from an unsubstituted furyl moiety, an optimization effort was undertaken with the aim of replacing the unsubstituted furan with a more metabolically stable group while maintaining potency and selectivity. Herein, we describe the synthesis and SAR of a range of novel heterocyclic systems and the successful identification of a replacement for the unsubstituted furan moiety with a methylfuran or thiazole moiety while maintaining potency and selectivity.
Journal of Medicinal Chemistry 04/2008; 51(6):1719-29. · 5.25 Impact Factor
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Deborah H Slee,
Manisha Moorjani,
Xiaohu Zhang,
Emily Lin,
Marion C Lanier,
Yongsheng Chen,
Jaimie K Rueter,
Sandra M Lechner,
Stacy Markison,
Siobhan Malany, [......],
Silvia Gual,
José-Luis Díaz,
Kayvon Jalali,
Yang Sai,
Zhiyang Zuo,
Chun Yang,
Jenny Wen,
Zhihong O'Brien,
Robert Petroski,
John Saunders
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ABSTRACT: Previously we have described a series of novel A 2A receptor antagonists with excellent water solubility. As described in the accompanying paper, the antagonists were first optimized to remove an unsubstituted furyl moiety, with the aim of avoiding the potential metabolic liabilities that can arise from the presence of an unsubstituted furan. This effort identified a series of potent and selective methylfuryl derivatives. Herein, we describe the further optimization of this series to increase potency, maintain selectivity for the human A 2A vs the human A 1 receptor, and minimize activity against the hERG channel. In addition, the observed structure-activity relationships against both the human and the rat A 2A receptor are reported.
Journal of Medicinal Chemistry 04/2008; 51(6):1730-9. · 5.25 Impact Factor
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Manisha Moorjani,
Xiaohu Zhang,
Yongsheng Chen,
Emily Lin,
Jaimie K Rueter,
Raymond S Gross,
Marion C Lanier,
John E Tellew,
John P Williams,
Sandra M Lechner,
Siobhan Malany,
Mark Santos,
Paddi Ekhlassi,
Julio C Castro-Palomino,
María I Crespo,
Maria Prat,
Silvia Gual,
José-Luis Díaz,
John Saunders, Deborah H Slee
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ABSTRACT: In this report, the design and synthesis of a series of pyrimidine based adenosine A(2A) antagonists are described. The strategy and outcome of expanding SAR exploration to attenuate hERG and improve selectivity over A(1) are discussed. Compound 33 exhibited excellent potency, selectivity over A(1), and reduced hERG liability.
Bioorganic & medicinal chemistry letters 03/2008; 18(4):1269-73. · 2.65 Impact Factor
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Deborah H Slee,
Xiaohu Zhang,
Manisha Moorjani,
Emily Lin,
Marion C Lanier,
Yongsheng Chen,
Jaimie K Rueter,
Sandra M Lechner,
Stacy Markison,
Siobhan Malany, [......],
Raymond S Gross,
John P Williams,
Julio C Castro-Palomino,
María I Crespo,
Maria Prat,
Silvia Gual,
José-Luis Díaz,
Jenny Wen,
Zhihong O'Brien,
John Saunders
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ABSTRACT: Potent adenosine hA2A receptor antagonists are often accompanied by poor aqueous solubility, which presents issues for drug development. Herein we describe the early exploration of the structure-activity relationships of a lead pyrimidin-4-yl acetamide series to provide potent and selective 2-amino-N-pyrimidin-4-yl acetamides as hA2A receptor antagonists with excellent aqueous solubility. In addition, this series of compounds has demonstrated good bioavailability and in vivo efficacy in a rodent model of Parkinson's disease, despite having reduced potency for the rat A2A receptor versus the human A2A receptor.
Journal of Medicinal Chemistry 03/2008; 51(3):400-6. · 5.25 Impact Factor
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ABSTRACT: The present article describes a selection of a new class of small molecule antagonists for the h-GnRH receptor, their preparation, and evaluation in vitro. Three computational methods were combined into a consensus score, to rank order virtual templates. The top 5% of templates were further evaluated in silico and assessed for novelty and synthetic accessibility. The tetrahydropyrido[4,3-d]pyrimidine-2,4-dione core was selected for synthesis and evaluated in vitro. Using an array approach for analog design and synthesis, we were able to drive the binding below 10nM for the h-GnRH receptor after two rounds of optimization.
Bioorganic & Medicinal Chemistry 09/2007; 15(16):5590-603. · 2.92 Impact Factor
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Jun-Young Choe,
Scott W Nelson,
Kristen L Arienti,
Frank U Axe,
Tassie L Collins,
Todd K Jones,
Rachel D A Kimmich,
Michael J Newman,
Karl Norvell,
William C Ripka,
Suzanne J Romano,
Kevin M Short, Deborah H Slee,
Herbert J Fromm,
Richard B Honzatko
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ABSTRACT: A highly constrained pseudo-tetrapeptide (OC252-324) further defines a new allosteric binding site located near the center of fructose-1,6-bisphosphatase. In a crystal structure, pairs of inhibitory molecules bind to opposite faces of the enzyme tetramer. Each ligand molecule is in contact with three of four subunits of the tetramer, hydrogen bonding with the side chain of Asp187 and the backbone carbonyl of residue 71, and electrostatically interacting with the backbone carbonyl of residue 51. The ligated complex adopts a quaternary structure between the canonical R- and T-states of fructose-1,6-bisphosphatase, and yet a dynamic loop essential for catalysis (residues 52-72) is in a conformation identical to that of the T-state enzyme. Inhibition by the pseudo-tetrapeptide is cooperative (Hill coefficient of 2), synergistic with both AMP and fructose 2,6-bisphosphate, noncompetitive with respect to Mg2+, and uncompetitive with respect to fructose 1,6-bisphosphate. The ligand dramatically lowers the concentration at which substrate inhibition dominates the kinetics of fructose-1,6-bisphosphatase. Elevated substrate concentrations employed in kinetic screens may have facilitated the discovery of this uncompetitive inhibitor. Moreover, the inhibitor could mimic an unknown natural effector of fructose-1,6-bisphosphatase, as it interacts strongly with a conserved residue of undetermined functional significance.
Journal of Biological Chemistry 01/2004; 278(51):51176-83. · 4.77 Impact Factor
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ABSTRACT: The regulation of lipid metabolism and it's effect on glucose control and diabetes has received intense interest. Hormone-sensitive lipase (HSL) is a vital enzyme in lipid metabolism. A series of novel pyrrolopyrazinediones has been discovered that demonstrate submicromolar activity both in the enzyme assay and in a (14)C-emulsion assay employing cholesteryl oleate as a substrate as a secondary measure of HSL activity. These compounds represent novel inhibitors of the human HSL enzyme.
Journal of Medicinal Chemistry 04/2003; 46(7):1120-2. · 5.25 Impact Factor
