May 20 - A.R. Haight

Combined Chemical Dictionary
Entry Name: Fiduxosin, INN
Synonym(s): 8-Phenyl-3-[4-(1,3a,4,9b-tetrahydro-9-methoxy[1]benzopyrano[3,4-c]pyrrol-2(3H)-yl)butyl]pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione, 9CI.
Molecular Formula: C30H29N5O4S
Molecular Weight: 555.656
Accurate Mass: 555.194025
Percentage Composition: C 64.85%; H 5.26%; N 12.60%; O 11.52%; S 5.77%
Biological Use/Importance: ?1a- and ?1D-Adrenoreceptor antagonist.
Used for the treatment of benign prostatic hyperplasia

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Variant: (3aR,9bR)-form
CAS Registry Number: 208993-54-8

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Derivative: Hydrochloride
Synonym(s): Fiduxosin hydrochloride, USAN
CAS Registry Number: 208992-74-9
Physical Description: Cryst. (MeOH)
Melting Point: Mp 291°

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References:

Pat. Coop. Treaty (WIPO), 1998, Abbott, 98 24 791
http://l2.espacenet.com/espacenet/viewer?PN=WO9824791&CY=ep&LG=en&DB=EPD
CA, 129, 67797r, (synth, pharmacol)

Arthur A. Hancock, et.al.,
Preclinical Pharmacology of Fiduxosin,
a Novel 1-Adrenoceptor Antagonist with Uroselective Properties
J Pharmacol Exp Ther 2002 300: 478-486.
http://jpet.aspetjournals.org/cgi/reprint/300/2/478.pdf

Michael E. Brune, et.al.,
Effect of Fiduxosin, an Antagonist Selective for 1A- and 1D-Adrenoceptors,
on Intraurethral and Arterial Pressure Responses in Conscious Dogs
J Pharmacol Exp Ther 2002 300: 487-494
http://jpet.aspetjournals.org/cgi/reprint/300/2/487.pdf

David G. Witte, et.al,
Modeling of Relationships between Pharmacokinetics and Blockade of Agonist-Induced Elevation of Intraurethral Pressure and Mean Arterial Pressure in Conscious Dogs Treated with 1-Adrenoceptor Antagonists
J Pharmacol Exp Ther 2002 300: 495-504.
http://jpet.aspetjournals.org/cgi/reprint/300/2/495.pdf

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SciFinder Scholar also gives a reference for the US Patent.
Meyer, Michael D.; Altenbach, Robert J.; Basha, Fatima Z.; Carroll, William A.; Drizin, Irene; Kerwin, James F., Jr.; Wendt, Michael D.; Haight, Anthony R.; Zhang, Weijiang.
Preparation of benzopyranopyrrolylalkylpyridothienopyrimidinediones and related compounds as a1 adrenergic antagonists. US 6046207 [CAN 132:265205]
http://l2.espacenet.com/espacenet/viewer?PN=US6046207&CY=ep&LG=en&DB=EPD

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Pteridines. XXXII.
2-Amino-3-cyano-5-chloromethylpyrazine 1-oxide and its conversion to 6-alkenyl-substituted pteridines
Edward C. Taylor, T. Kobayashi;
J. Org. Chem.; 1973; 38(16); 2817-2821.
http://pubs.acs.org/cgi-bin/archive.cgi/joceah/1973/38/i16/pdf/jo00956a018.pdf

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[FR] 2-AZA-1,3-DIENES - A NEW APPROACH TO SUBSTITUTED 2-AMINOPYRAZINES
LANG M, SCHOENI JP, PONT C, FLEURY JP
HELVETICA CHIMICA ACTA
69 (4): 793-802 1986

Week 7

May 15 - Peter Dragovitch

***Cysteine Peptidases (Chapter 185) in:
Handbook of Proteolytic Enzymes
http://skinbark.caltech.edu/cdroms/Handbook_of_Proteolytic_Enzymes/_campus_access/
Page down (in the top screen) to chapter 185 and click on Cysteine Peptidases to display text.

1. Recent advances in the development of human rhinovirus 3C protease inhibitors.    
Dragovich, Peter S..   
Expert Opinion on Therapeutic Patents  (2001),  11(2),  177-184. 
MIL-1 RESERVE
A review with 52 refs.  The human rhinoviruses (HRVs) are the most significant cause of the common cold.  Important advances in the development of novel, broad spectrum antirhinoviral agents have recently been made by inhibiting the function of virally encoded enzymes essential for viral replication.  This article summarizes the most recent developments in the design of HRV 3C protease inhibitors which are intended for use as broad spectrum antirhinoviral therapeutic agents. 

2. Design of rhinovirus protease inhibitors for the treatment of the common cold.    
Wang, Q. May.   
Drugs of the Future  (2000),  25(3),  279-286. 
Abstract
A review with 86 refs.  Human rhinoviruses (HRVs) are the major cause of the common cold in humans.  As members of the picornaviral family, HRVs are a group of small single-stranded RNA viruses.  From their genome, a polyprotein precursor can be synthesized and further processed mainly by 2 viral proteases designated 2A and 3C.  The 2A protease (2Apro) makes the first cleavage between the structural and nonstructural proteins, while 3C protease (3Cpro) governs most of the remaining internal cleavages.  Both 2Apro and 3Cpro are classified as cysteine proteases but their overall protein folding is more like typical serine proteases.  Their unique protein structure and essential roles in viral replication make them excellent targets for antiviral intervention.  In recent years, compds. inhibiting 2A and 3C protease activity have been identified through high-throughput screening and rational design.  This article summarizes the most recent approaches in the design of novel 2A and 3C protease inhibitors as potential antiviral agents for the treatment of the common cold. 

3. Human rhinovirus 3C protease inhibitors: recent developments
Wang QM
EXPERT OPINION ON THERAPEUTIC PATENTS
8 (9): 1151-1156 SEP 1998
MIL-1 RESERVE
Abstract:
As members of the picomavirus family, human rhinoviruses (HRVs) are the major cause of the common cold in humans. In recent years, considerable efforts have been made in the development of anti-HRV compounds targeting rhinovirus enzymes including the viral proteases essential for viral replication. This article summarises the most recent approaches in designing novel HRV 3C protease inhibitors for the treatment of rhinovirus infections.

4. Vinylogous amino acid esters: a new class of inactivators for thiol proteases
Robert P. Hanzlik, Stewart A. Thompson;
J. Med. Chem.; 1984; 27(6); 711-712.
http://pubs.acs.org/cgi-bin/archive.cgi/jmcmar/1984/27/i06/pdf/jm00372a001.pdf

5. Vinyl Sulfones as Mechanism-Based Cysteine Protease Inhibitors
James T. Palmer, David Rasnick, Jeffrey L. Klaus, Dieter Bromme;
J. Med. Chem.; 1995; 38(17); 3193-3196.
http://pubs.acs.org/cgi-bin/archive.cgi/jmcmar/1995/38/i17/pdf/jm00017a002.pdf

6. MG Cordingley, PL Callahan, VV Sardana, VM Garsky, and RJ Colonno
Substrate requirements of human rhinovirus 3C protease for peptide cleavage in vitro
J. Biol. Chem., Jun 1990; 265: 9062 - 9065.
http://www.jbc.org/cgi/reprint/265/16/9062.pdf

7. Synthetic and enzyme inhibition studies of pepstatin analogs containing hydroxyethylene and ketomethylene dipeptide isosteres
Mark W. Holladay, Francesco G. Salituro, Daniel H. Rich;
J. Med. Chem.; 1987; 30(2); 374-383.
http://pubs.acs.org/cgi-bin/archive.cgi/jmcmar/1987/30/i02/pdf/jm00385a020.pdf

8. Peptide mimetics - tailor-made enzyme inhibitors.    
Gante, Joachim. 
Angewandte Chemie  (1994),  106(17),  1780-802
Angew. Chem., Int. Ed. Engl., 1994, 33(17), 1699-720).
Abstract
A review with many refs., on the design, prepn., and enzyme inhibitory mechanisms of peptide mimetics. 

9. Structure-Based Design, Synthesis, and Biological Evaluation of Irreversible Human Rhinovirus 3C Protease Inhibitors.
4. Incorporation of P1 Lactam Moieties as L-Glutamine Replacements
Dragovich, P. S.; et.al.
J. Med. Chem.; (Article); 1999; 42(7); 1213-1224.
http://pubs.acs.org/cgi-bin/article.cgi/jmcmar/1999/42/i07/pdf/jm9805384.pdf

Week 6

May 6 - Brad Henke

The first 3 references refer to short articles in the "Nature Encyclopedia of Life Sciences"

< www.els.net > search term = diabetes

1. Insulin Action: Molecular Basis of Diabetes
Najjar, Sonia
Unbalanced regulation of the signalling cascades that mediate insulin action in the cell leads to diabetes mellitus. Thus, identification of the basic mechanism of insulin action promotes our understanding of the molecular basis of diabetes and the development of better therapeutic interventions.

2. Insulin and Glucagon
Brady, Matthew J and Saltiel, Alan R
Insulin and glucagon are reciprocal hormones which regulate plasma glucose concentrations. Together, these hormones maintain blood glucose in a narrow range, despite wide variances in glucose production and utilization by the body.

3. History of Insulin
Sneader, Walter
Failure of the pancreas to produce sufficient insulin results in high blood sugar levels and the development of diabetes. The isolation of insulin in 1922 provided a means of treating diabetes by administering daily injections of the hormone.

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The PPARs: From orphan receptors to drug discovery.
Willson, Timothy M.; Brown, Peter J.; Sternbach, Daniel D.; Henke, Brad R..
Glaxo Wellcome Research & Development, Research Triangle Park, NC, USA.
Journal of Medicinal Chemistry (2000), 43(4), 527-550.
http://pubs.acs.org/cgi-bin/article.cgi/jmcmar/2000/43/i04/pdf/jm990554g.pdf

Abstract

A review with 326 refs. is given on peroxisome proliferator-activated receptors (PPARs). The structural and functional anal. of the different PPAR subtypes is summarized and their function as hormone receptors for dietary fatty acids and certain eicosanoids in different species and in many metabolically active tissues is described. Progress is reported in the development of drugs, which use PPARs as mol. targets, for the treatment of human metabolic diseases.

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PPAR agonists in health and disease: a pathophysiologic and clinical overview.
Mudaliar, Sunder; Henry, Robert R. VA San Diego HealthCare System, Section of Diabetes/Metabolism,
University of California at San Diego, San Diego, CA, USA.
Current Opinion in Endocrinology & Diabetes (2002), 9(4), 285-302.

Abstract

A review. The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that control energy metab. through genomic effects. Studies in animals and humans have demonstrated a physiol. role for these receptors in functions varying from adipogenesis to lipid metab. to vascular biol. and atherosclerosis progression. The PPAR ligands in clin. use today-the fibric acid derivs. (PPAR.alpha. agonists) and the thiazolidinediones (TZDs) (PPAR.gamma. agonists) are widely used for their lipid-lowering and glycemic effects, resp. There is now growing evidence that in addn. to these effects, these agents as PPAR ligands may favorably alter the atherosclerosis process and potentially reduce cardiovascular morbidity and mortality. In the future, given our current knowledge of selective PPAR agonists, it is possible to envisage the availability of tailored PPAR compds. which through their selective agonist effects will have enhanced beneficial effects on glucose, lipid, and vascular endothelial metab. and through their partial agonist, or even selective antagonist actions, will not possess the unwanted side effects of wt. gain and fluid retention currently seen with the PPAR.gamma. agonists. Equally exciting is the possibility of a role for these agents in immune-mediated diseases and cancer.

 

May 8 - Matt Sharp

Farglitazar; GI 262570; GI 262570X
L-Tyrosine, N-(2-benzoylphenyl)-O-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]- (9CI)
Registry Number: 196808-45-4
SciFinder Scholar

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Combined Chemical Dictionary

http://www.chemnetbase.com/scripts/ccdweb.exe

Entry Name: Farglitazar, INN, USAN
Synonym(s): N-(2-Benzoylphenyl)-O-[1-(5-methyl-2-phenyl-4-oxazolyl)ethyl]tyrosine, 9CI. GI 262570X
Molecular Formula: C34H30N2O5
Molecular Weight: 546.621
Percentage Composition: C 74.71%; H 5.53%; N 5.12%; O 14.63%
Biological Use/Importance: PPAR ? receptor agonist. Insulin action enhancer used in the treatment of Type II diabetes
Variant: (S)-form
Synonym(s): L-form
CAS Registry Number: 196808-45-4
Melting Point: Mp 148-150°

References:

Pat. Coop. Treaty (WIPO), 1997, Glaxo, 97 31 907
CA, 127, 278064w, (synth, pharmacol)
Collins, J.L. etal., J. Med. Chem., 1998, 41, 5020-5036; 5037-5054; 5055-5069, (synth, pharmacol)
N-(2-Benzoylphenyl)-L-tyrosine PPARg Agonists.

1. Discovery of a Novel Series of Potent Antihyperglycemic and Antihyperlipidemic Agents.
http://pubs.acs.org/cgi-bin/gap.cgi/jmcmar/1998/41/i25/pdf/jm9804127.pdf

2. Structure-Activity Relationship and Optimization of the Phenyl Alkyl Ether Moiety.
http://pubs.acs.org/cgi-bin/gap.cgi/jmcmar/1998/41/i25/pdf/jm980413z.pdf

3. Structure-Activity Relationship and Optimization of the N-Aryl Substituent.
http://pubs.acs.org/cgi-bin/gap.cgi/jmcmar/1998/41/i25/pdf/jm980414r.pdf

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Crystallization

Section: Crystal Characteristics
Author: Joachim Ulrich
Kirk-Othmer Encyclopedia of Chemical Technology
http://www.mrw.interscience.wiley.com/kirk/articles/crysrous.a01/sect1_4-fs.html

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Novel process for preparing and harvesting crystalline pharmaceutical particles. Lancaster, Robert William; Singh, Hardev; Theophilus, Andrew Lewis. (Glaxo Group Limited, UK). PCT Int. Appl. (2002). WO 0200199

Abstract
The present invention relates to a novel process for prepg. and harvesting cryst. particles, particularly pharmaceutical or carrier substances of a size suitable for inhalation therapy. Fluticasone propionate was dissolved in hot acetone and then allowed to cool to ambient temp. A flow cell was then charged with a 4:1 mixt. of water and acetone. Pump 1 (contg. the fluticasone propionate in acetone) was set at a flow rate of 20 mL/min. Pump 2 (contg. chilled water) was set at 80 mL/min. An ultrasound probe was set to deliver approx. 70-75 W of power. When the ultrasound probe and both pumps were turned on, rapid onset of crystn. occurred. The slurry output was collected in a flask and concd. in vacuo until all of the acetone had been removed, leaving only aq. slurry. The contents of the flask were then freeze dried overnight to give a free flowing fine dry white powder. No sieving or deaggregation of the particles by passing them through a screen was necessary.

http://l2.espacenet.com/espacenet/viewer?PN=WO0200199&CY=ep&LG=en&DB=EPD

Week of April 21 References:

Norbeck, Daniel W.
Progress toward the total synthesis of polyether ionophore antibiotics.
CIT theses ; 1985. 

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Standardization Protocols and Optimized Precursor Sets for the Efficient Application of Automated Parallel Synthesis to Lead Optimization:
A Mitsunobu Example
Gentles, R. G.; Wodka, D.; Park, D. C.; Vasudevan, A.;
J. Comb. Chem.; 2002; 4(5); 442-456.
http://pubs.acs.org/cgi-bin/article.cgi/jcchff/2002/4/i05/pdf/cc010090j.pdf
Supporting Information
http://pubs.acs.org/cgi-bin/suppinfo.pl?cc010090j

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Purification of HTOS libraries by supercritical fluid chromatography
Hochlowski J, Olson J, Pan J, Sauer D, Searle P, Sowin T
JOURNAL OF LIQUID CHROMATOGRAPHY & RELATED TECHNOLOGIES
26 (3): 333-354 2003
Abstract
A commercially available preparative scale supercritical fluid chromatography (SFC) system has been customized and applied to the purification of high throughput organic synthesis (HTOS) libraries. Pilot reactions allow the triage between HPLC and SFC as the most appropriate purification technique, and when applicable, SFC has been proven to offer advantages in terms of decreased purification and sample dry-down time and purification capabilities, somewhat complementary to HPLC. Standardized chemistry-specific SFC methods have been determined and HTOS pilot reactions allow refinement of these standard methods to optimal conditions for a specific library core.

Week of April 14 References:

Delaney

Triamcinolone
124-94-7
Pregna-1,4-diene-3,20-dione,
9-fluoro-11,16,17,21-tetrahydroxy-, (11b,16a)- (9CI)

A REINVESTIGATION OF THE D-HOMOANNULAR REARRANGEMENT AND SUBSEQUENT DEGRADATION PATHWAYS OF (11-BETA,16-ALPHA)-9-FLUORO-11,16,17,21-TETRAHYDROXYPREGNA-1,4-DIENE-3,20-DIONE (TRIAMCINOLONE)
DELANEY EJ, SHERRILL RG, PALANISWAMY V, SEDERGRAN TC, TAYLOR SP
STEROIDS
59 (3): 196-204 MAR 1994
Abstract:
The commercial anti-inflammatory drug triamcinolone has been shown to rearrange by similar, but distinct pathways when exposed to certain trace metal ions or to dilute aqueous base. In the presence of aqueous base, the 16-hydroxy-20-keto system undergoes reverse aldol cleavage of the 16,17-bond, followed by aldol cyclization linking C-16 to C-20. This base-catalyzed rearrangement gives a 16 beta,17 alpha-dihydroxy product and a corresponding 16 alpha,17 alpha-dihydroxy product in roughly 4 to 1 ratio. Metal-catalyzed rearrangement provides the 16 alpha,17 alpha-dihydroxy product with exremely high stereoselectivity. Mechanistic models are propsed that help explain the ratio of products isolated from each route. The studies presented suggest that similar forms of rearrangement could be of preparative value in syntheses requiring specific stereochemistry of appropriately substituted bicyclic alpha,beta-dihydroxyketones. Under more vigorous conditions of aqueous base treatment these rearrangement products undergo further decomposition with loss of formaldehyde from the hydroxymethyl group, followed by beta-elimination of water. Reaction of the beta-elimination product with formaldehyde results in the formation of a dimeric species linked by a methylene group.

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Tipredane
85197-77-9
Androsta-1,4-dien-3-one,
17-(ethylthio)-9-fluoro-11-hydroxy-17-(methylthio)-, (11b,17a)- (9CI) 

Optimization of cosolvent concentration and excipient composition in a topical corticosteroid solution.    
Varia, Sailesh A.; Faustino, Marilia M.; Thakur, Ajit B.; Clow, Charles S.; Serajuddin, Abu T. M.   
Pharm. Res. Dev. Dep.,  Bristol-Myers Squibb Pharm. Res. Inst.,  New Brunswick,  NJ,  USA.   
Journal of Pharmaceutical Sciences  (1991),  80(9),  872-5. 
Abstract
Physiochem. factors involved in the development of a topical soln. of a novel corticosteroid, tipredane (I), are described.  A cosolvent system consisting of polyethylene glycol 400 (PEG 400), propylene glycol, and water was used to dissolve the concn. (0.1% w.w.) of I required for the formulation.  The solvent mixt. was also nonirritating to the skin.  A buffering agent, antioxidant, and metal-chelating agent were required to stabilize the drug.  Solubilities of hydrophilic and lipophilic excipients were ensured by careful adjustment of their concns., as well as that of PEG 400.  Two formulations, one contg. K citrate and the other tromethamine as the buffering agents, were identified.  Upon storage, Na metabisulfite, an antioxidant used in the formulation, oxidized to form K2SO4 in the formulation contg. K citrate.  K citrate decreased the soly. and resulted in the pptn. of K2SO4 by exerting a common ion effect.  Lowering of the concns. of K citrate, Na metabisulfite, and PEG 400 ensured the soly. of K2SO4 formed.  There was no such pptn. of K2SO4 in the formulation buffered with tromethamine, thus indicating that tromethamine is a good buffering agent in cosolvent systems.

--------------------------------

Fluorine Compounds, Inorganic, Boron Trifluoride
Kirk-Othmer Encyclopedia of Chemical Technology, 3rd edition
1980, v.10, p.685-693

Fluorine Compounds, Inorganic, Boron Trifluoride
Kirk-Othmer Encyclopedia of Chemical Technology, 4th edition
http://www.mrw.interscience.wiley.com/kirk/articles/boroevan.a01/sect1_8-fs.html

Boron Compounds. Boron Halides
Ullmann's Encyclopedia of Industrial Chemistry, 6th
http://www.mrw.interscience.wiley.com/ueic/articles/a04_309/sect1-fs.html

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Decicco

Identification of a Selectivity Determinant for Inhibition of Tumor Necrosis Factor-alpha Converting Enzyme by Comparative Modeling.
Zelda R. Wasserman, ..., Carl P. Decicco
Chemistry & Biology, 10 (3) (2003) pp. 215-223
http://www.elsevier.nl/gej-ng/10/14/33/83/48/31/article.pdf

Drugs (from the Dictionary of Drugs)

Etanercept, BAN
Synonym(s): Enbrel. TNF-001. TNFR-Fc
Chapman & Hall Number: GQO18-W
CAS Registry Number: 185243-69-0
Type of Compound Code(s): XA4750
General Statement: Recombinant tumour necrosis factor receptor Fc Fusion protein
Biological Use/Importance: First specific anti-cytokine therapy approved for use in the treatment of rheumatoid arthritis
Development Status: Marketed drug. Approved 1998. Worldwide 69th best selling prescription drug ($0.76 bn, 2001) (Immunex) (Pharma Business)
Other: Immunex Corp.

References:
Sorbera, L.A. etal., Drugs of the Future, 1998, 23, 951-954
Jarvis, B. etal., Drugs, 1999, 57, 945-966, (rev)
Moreland, L.W., Expert Opin. Invest. Drugs, 1999, 8, 1443-1451
Weinblatt, M.E. etal., N. Engl. J. Med., 1999, 340, 253-259, (clin trial)
Calin, A., J. Drug Eval. Rheumatol., 2001, 1, 13-40, (rev, pharmacol)

Entry Name: Infliximab
Synonym(s): Remicade, 9CI
Chapman & Hall Number: HOK36-D
CAS Registry Number: 170277-31-3
Type of Compound Code(s): XA4780
General Statement: Chimeric monoclonal antibody to tumour necrosis factor ?
Biological Use/Importance: Used in the treatment of Crohn's disease and rheumatoid arthritis
Development Status: Marketed drug. Approved for clinical use in the EU (1999). Worldwide 76th best selling prescription drug ($0.72 bn, 2001) (Johnson and Johnson) (Pharma Business)

References:
Van Hogezand, R.A. etal., Drugs, 1998, 56, 299-305, (pharmacol)
D'Haens, G. etal., Gastroenterology, 1999, 116, 22-28 1029-1034, (pharmacol)
Moreland, L.W. etal., J. Rheumatol. Suppl., 1999, 57, 7-15, (rev)
Maini, R., Lancet, 1999, 354, 1932-1939, (pharmacol)
Markham, A. etal., Drugs, 2000, 59, 1341-1359, (rev)

 

Week of April 7 References: