CHEM 4347, Spring 2007
Advanced Interdisciplinary Topics
Drug Design

MEB 105
9:55 11:10 TTh

Instructors:

 
Dr. Steven Bachrach
215D MEB
999-7379
sbachrach@trinity.edu
Office Hours: MWF 1:00-2:00pm
      or by appointment
Dr. Adam Urbach
215B MEB
999-7660
aurbach@trinity.edu
Office Hours: MWF 12:00-1:00pm
      or by appointment

Textbook: An Introduction to Medicinal Chemistry, 3rd Edition, Graham Patrick, Oxford University Press: Oxford, UK, 2005

Course Description:

This senior-level course will present the major concepts involved in modern drug design, primarily through case study. A major feature of the class will be how multiple chemical subdisciplines biochemistry, organic synthesis, physical chemistry, computational chemistry, chemometrics combine to solve drug design problems.

Topics and Schedule:

The following is a list of topics, recommended reading, and the tentative weeks that these topics will be discussed in class.

Week 1: Introduction to Drug Design Principles, ADME/Tox
      Patrick: Chapter 12.1, Chapter 8

Week 2-3: Introduction to Protein Structure, Function, Thermodynamics and Kinetics
      Patrick: Chapter 2.3, Chapter 10.1

Week 4-5: Introduction to QSAR, Docking and Crystallography
      Patrick: Chapter 13

Weeks 6-16: Case studies of various drug developments. We will discuss a number of different drugs and different diseases targeted by researchers. This core portion of the class will involve extensive reading of the primary chemistry, biochemistry, and biology literature. Relevant chapters from the Patrick text will be utilized. Students will be asked to prepare to lead and participate in class discussions. This portion of the class will be much more like a seminar than a lecture class.

Web Site: http://www.trinity.edu/sbachrac/drugdesign2007

Grading: Your grade will be determined in the following manner:

Mid-Term Exam100 points
Final Term Paper100 points

Class Participation

200 points
Total400 points

The Mid-Term Exam will be held following the QSAR/docking/crystallography section, approximately during the 6th week of class. This will be a written exam and is worth one-quarter of the overall grade. A term paper will be due on the last day of class. Further information on the length, scope, and topics of this paper will be presented about midway through the semester. This paper will be worth one-quarter of the overall grade.

The remainder of your grade will be based on your class participation. Students are expected to come to class prepared to discuss the pertinent topics of the day. During the last portion of the semester we will discuss case studies of various pharmaceuticals, their design strategies, their syntheses, and their successes and failures. Each student will act as discussion leader for two classes. The discussion leader will be expected to come to class ready to describe the relevant literature, to promote and guide the class discussion, and to ask questions and make comments. For the first pass through the group of student discussion leaders, you will be assigned a major paper from the chemical literature, but will likely have to read additional references to properly place the major paper in its proper context. For the second pass through the group, each student will select their own paper, with approval of either professor. Students who are not leading the discussion are expected to be prepared to participate in the discussions. Your level of participation, your ability as discussion leader, and the insight you display will be evaluated and will comprise one-half of your course grade.

Class PowerPoint Presentations:

Web resources:

Drug costs

Multiple Regression Software

    Downolad this zipped file. After you unzip it, you will find four files: Nonlin.exe, Nonlin.doc, Read.me, and HeatForm.NLR. The first file (Nonlin.exe) is the actually program that performs the regression analysis. The Nonlin.doc file is a MS Word file that describes the use of the program in detail. The Read.me file is a very short description of getting started with the program. The last file (HeatForm.NLR) is the data file that you will analize. It contains the heats of formation for a number of alkanes, along with the number of carbon and hydrogen atoms.
                 

Student-led discussion papers

  1. "Discovery of a Potent Inhibitor of the Antiapoptotic Protein Bcl-xL from NMR and Parallel Synthesis," J. Med. Chem., 2006, 49, 656, DOI: 10.1021/jm0507532.
  2. "SAR and Mode of Action of Novel Non-Nucleoside Inhibitors of Hepatitis C NS5b RNA Polymerase," J. Med. Chem., 2006, 49, 1034, DOI: 10.1021/jm050859x.
  3. Discovery of 1-[3-(Aminomethyl)phenyl]-N-[3-fluoro-2'-(methylsulfonyl)- [1,1'-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC423), a Highly Potent, Selective, and Orally Bioavailable Inhibitor of Blood Coagulation Factor Xa1," J. Med. Chem., 2001, 44, 566, DOI: 10.1021/jm000409z.
  4. "Anilinoquinazoline Inhibitors of Fructose 1,6-Bisphosphatase Bind at a Novel Allosteric Site: Synthesis, In Vitro Characterization, and X-ray Crystallography," J. Med. Chem., 2002, 45, 3865, DOI: 10.1021/jm010496a.
  5. "Discovery of Imidazo[1,2-b][1,2,4]triazines as GABAA 2/3 Subtype Selective Agonists for the Treatment of Anxiety", J. Med. Chem., 2006, 49, 1235, DOI: 10.1021/jm051200u.
  6. "Design and Biological Activity of (S)-4-(5-{[1-(3-Chlorobenzyl)-2- oxopyrrolidin-3-ylamino]methyl}imidazol-1-ylmethyl)benzonitrile, a 3-Aminopyrrolidinone Farnesyltransferase Inhibitor with Excellent Cell Potency," J. Med. Chem., 2001 44, 2933, DOI: 10.1021/jm010156p.
  7. "Viracept (Nelfinavir Mesylate, AG1343): A Potent, Orally Bioavailable Inhibitor of HIV-1 Protease," J. Med. Chem., 1997, 40, 3979, DOI: 10.1021/jm9704098.
  8. "The discovery of potent nonpeptide angiotensin II receptor antagonists: a new class of potent antihypertensives," J. Med. Chem., 1990, 33, 1312. DOI: 10.1021/jm00167a007.
  9. "Structure-Based Design of Cathepsin K Inhibitors Containing a Benzyloxy-Substituted Benzoyl Peptidomimetic," J. Med. Chem., 1998, 41, 3923, DOI: 10.1021/jm980474x.
  10. "L-735,524: The Design of a Potent and Orally Bioavailable HIV Protease Inhibitor," J. Med. Chem., 1994, 37, 3443, DOI: 10.1021/jm00047a001.
  11. "The discovery of rofecoxib, [MK 966, Vioxx, 4-(4'-methylsulfonylphenyl)-3-phenyl-2(5H)-furanone], an orally active cyclooxygenase-2 inhibitor," Bioorganic & Medicinal Chemistry Letters, 1999, 9, 1773, http://www.trinity.edu/sbachrac/drugdesign/paper1.pdf.
  12. "Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents," Nature, 1996, 384, 644, http://www.trinity.edu/sbachrac/drugdesign/paper2.pdf .
  13. "cis-2,5-Dicyanopyrrolidine Inhibitors of Dipeptidyl Peptidase IV: Synthesis and in Vitro, in Vivo, and X-ray Crystallographic Characterization," J. Med. Chem., 2006, 49, 3068, DOI: 10.1021/jm0600085.
  14. "Discovery, Structure-Activity Relationship, and Pharmacological Evaluation of (5-Substituted-pyrrolidinyl-2-carbonyl)-2-cyanopyrrolidines as Potent Dipeptidyl Peptidase IV Inhibitors," J. Med. Chem., 2006, 49, 3520, 2006. DOI: 10.1021/jm051283e.
  15. "2-Aminothiazole as a Novel Kinase Inhibitor Template. Structure-Activity Relationship Studies toward the Discovery of N-(2-Chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl)]-2-methyl-4-pyrimidinyl]amino)]-1,3-thiazole-5-carboxamide (Dasatinib, BMS-354825) as a Potent pan-Src Kinase Inhibitor," J. Med. Chem., 2006, 49, 6819 DOI: 10.1021/jm060727j.
                 

Papers for Class Discussion on February 27

  1. "Thienothiopyran-2-sulfonamides: novel topically active carbonic anhydrase inhibitors for the treatment of glaucoma," J. Med. Chem., 1989, 32, 2510 DOI: 10.1021/jm00132a003.
  2. "Thienothiopyran-2-sulfonamides: a novel class of water-soluble carbonic anhydrase inhibitors," J. Med. Chem., 1987, 30, 591 DOI: 10.1021/jm00387a002.
                 

Class discussion schedule

Thursday 3/1 - Sarah
        "SAR and Mode of Action of Novel Non-Nucleoside Inhibitors of Hepatitis C NS5b RNA Polymerase," J. Med. Chem., 2006, 49, 1034, DOI: 10.1021/jm050859x.

Tuesday 3/6 - Matt
        "Discovery, Structure-Activity Relationship, and Pharmacological Evaluation of (5-Substituted-pyrrolidinyl-2-carbonyl)-2-cyanopyrrolidines as Potent Dipeptidyl Peptidase IV Inhibitors," J. Med. Chem., 2006, 49, 3520, 2006. DOI: 10.1021/jm051283e.

Tuesday 3/6 - Nicole
        "The discovery of potent nonpeptide angiotensin II receptor antagonists: a new class of potent antihypertensives," J. Med. Chem., 1990, 33, 1312. DOI: 10.1021/jm00167a007.

Thursday 3/8 - Bethany
        "Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents," Nature, 1996, 384, 644, http://www.trinity.edu/sbachrac/drugdesign/paper2.pdf .

Thursday 3/8 - Christina
        "Viracept (Nelfinavir Mesylate, AG1343): A Potent, Orally Bioavailable Inhibitor of HIV-1 Protease," J. Med. Chem., 1997, 40, 3979, DOI: 10.1021/jm9704098.

Tuesday 3/20 - Sharon
        "Anilinoquinazoline Inhibitors of Fructose 1,6-Bisphosphatase Bind at a Novel Allosteric Site: Synthesis, In Vitro Characterization, and X-ray Crystallography," J. Med. Chem., 2002, 45, 3865, DOI: 10.1021/jm010496a.

Tuesday 3/20 - Brian
        "The discovery of rofecoxib, [MK 966, Vioxx, 4-(4'-methylsulfonylphenyl)-3-phenyl-2(5H)-furanone], an orally active cyclooxygenase-2 inhibitor," Bioorganic & Medicinal Chemistry Letters, 1999, 9, 1773, http://www.trinity.edu/sbachrac/drugdesign/paper1.pdf.

Thursday 3/22 - Brian
        "Discovery of Imidozo[1-2-b][1,2,4]triazines as GABA Selective Agonists for the Treatment of Anxiety," J. Med Chem., 2006, 49, 1235-1238, DOI: 10.1021/jm051200u.

Tuesday 3/27 - Bethany
        "2-Phenyl-2-(1-hydroxycycloalkyl)ethylamine derivatives: synthesis and antidepressant activity," J. Med. Chem., 1990, 33, 2899-2905 DOI: 10.1021/jm00172a035

Thursday 3/29 - Christina
        "Evaluation of 8-Arylsulfanyl, 8-Arylsulfoxyl, and 8-Arylsulfonyl Adenine Derivatives as Inhibitors of the Heat Shock Protein 90," J. Med. Chem., 2005, 48, 2892-2905. DOI: 10.1021/jm049012b

Tuesday 4/3 - Sarah
        "Evolution of a Highly Selective and Potent 2-(Pyridin-2-yl)-1,3,5-triazine Tie-2 Kinase Inhibitor," J. Med. Chem., 2007, 50, 611-626. DOI: 10.1021/jm061107l

Thursday 4/5 - Nicole
        "Structure-Activity Relationships of the Quinolone Antibacterials against Mycobacteria: Effect of Structural Changes at N-1 and C-7," J. Med. Chem., 1996, 39, 729-735 DOI: 10.1021/jm9507082

Tuesday 4/10 - Matt
       2-Aminothiazole as a Novel Kinase Inhibitor Template. Structure-Activity Relationship Studies toward the Discovery of N-(2-Chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1- piperazinyl)]-2-methyl-4-pyrimidinyl]amino)]-1,3-thiazole-5-carboxamide (Dasatinib, BMS-354825) as a Potent pan-Src Kinase Inhibitor," J. Med. Chem., 2006, 49, 6819-6832, DOI: 10.1021/jm060727j

Thursday 4/12 - Sharon
        "Synthesis, Structure-Activity Relationships, and Pharmacological Evaluation of Pyrrolo[3,2,1-ij]quinoline Derivatives: Potent Histamine and Platelet Activating Factor Antagonism and 5-Lipoxygenase Inhibitory Properties. Potential Therapeutic Application in Asthma," J. Med. Chem., 1995, 38, 669-685, DOI: 10.1021/jm00004a013

Tuesday 4/17 - Nicole
        "Polyester Dendritic Systems for Drug Delivery Applications: In Vitro and In Vivo Evaluation," Bioconjugate Chem., 2002, 13, 453-461. DOI: 10.1021/bc010103m.

Tuesday 4/17 - Christina
        "Temporal targeting of tumour cells and neovasculature with a nanoscale delivery system," Nature, 2005, 436, 568-572.

Thursday 4/19 - Matt
        "The Discovery of Tadalafil: A Novel and Highly Selective PDE5 Inhibitor. 1: 5,6,11,11a-Tetrahydro-1H-imidazo[1',5':1,6]pyrido[3,4-b]indole-1,3(2H)-dione Analogues," J. Med. Chem., 2003, 46, 4525-4532, DOI: 10.1021/jm030056e

        "The Discovery of Tadalafil: A Novel and Highly Selective PDE5 Inhibitor. 2: 2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione Analogues," J. Med. Chem., 2003, 46, 4533-4542. DOI: 10.1021/jm0300577.

Thursday 4/19 - Brian (NEW)
        "Design, Synthesis, and Crystal Structure of Hydroxyethyl Secondary Amine-Based Peptidomimetic Inhibitors of Human β-Secretase," J. Med. Chem., 2007, 50, 776-781. DOI: 10.1021/jm061242y

Tuesday 4/24 - Sarah
        "Synthesis and Pharmacology of Ethylphenidate Enantiomers: The Human Transesterification Metabolite of Methylphenidate and Ethanol," J. Med. Chem., 2005, 48, 2876-2881. DOI: 10.1021/jm0490989.

Thursday 4/26 - Sharon
        "Varenicline: An 42 Nicotinic Receptor Partial Agonist for Smoking Cessation," J. Med. Chem., 2005, 48, 3474-3477, DOI: 10.1021/jm050069n

Thursday 4/26 - Bethany
        "N-[3-(2-Dimethylaminoethyl)-2-methyl-1H- indol-5-yl]-4- fluorobenzamide: A Potent, Selective, and Orally Active 5-HT1F Receptor Agonist Potentially Useful for Migraine Therapy," J. Med. Chem., 2001, 44, 4031-4034. DOI: 10.1021/jm0155190.

        "Isochroman-6-carboxamides as Highly Selective 5-HT1D Agonists: Potential New Treatment for Migraine without Cardiovascular Side Effects," J. Med. Chem., 1998, 41, 2180-2183. DOI: 10.1021/jm980137o.