Transcript Chemistry 910 Practical Medicinal Chemistry

Chemistry 910
Practical Medicinal
Chemistry
Dr John Carran
Queen’s University
Department of Chemistry
Background
 In
conjunction with Dale Cameron
 To develop a course to teach the
fundamentals of medicinal chemistry
and then to apply them
 Lecture component
 Practical component
Lecture component
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Where do drugs act
How do drugs bind
How are drugs metabolised/consequences
How are drugs administered/consequences
How are drugs tested
SAR/QSAR
Molecular modeling (Mike Kuiper, Melbourne, Australia)
Lead compound generation/drug design
Chemistry and improving activity/drug design
Business/intellectual property (Angela Lyon, Parteq,
Queen’s University)
Process/scale up
Clinical trials
Case studies
Practical component
Aim: To mimic an industrial lead
compound selection process. Opiate
analgesics.
 Each week for 5 weeks a series of
compounds with associated data is
released.
 Each “company” must select one
compound to progress in their pipeline to
lead compound designation
 Each company must rationalise their
selection process to a Medicinal Chemistry
mentor.
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Mentors
 Dale
Cameron - Migenix Corp
 Jack Bikker – Wyeth Research
 Harold Mastalertz – BMS
Dinesh Vyas
 Sheldon Hiebert – BMS
Rick Friesen
 Sheldon Crane – Merck
Video conferencing
 One
per week, weeks 7-11
 Skype or VSee (Free!)
 Each “company” has 30 minutes
 Questions from mentor on selection
process / red herrings
 Teaching component
 Evaluations on “company” and
individual members returned to me
“Red Herrings”
Sample compound information
Effective dose
effective dose ED50 behavioural symptoms rhesus monkey intramuscular
ED50 0.0014 mg/kg, behavioural symptoms Saimiri sciureus,
squirrel monkey intramuscular ED50 0.0018 mg/kg, agonist HEK293
cells transfected with hδOR EC50 727 pmol/l, peristaltic
stimulant Sprague-Dawley rat Subcutaneous ED50
0.247 mg/kg, peristaltic stimulant Sprague-Dawley rat
Subcutaneous ED50 0.964 mg/kg, Antinociceptive
Sprague-Dawley rat Subcutaneous ED50 0.003 mg/kg,
{effective dose ED50 Antinociceptive used as methane
sulfonate in Macaca mulatta, rhesus monkey ED50 1.0
μg}
Activity
Narcotic Analgesic
Rotation/refraction
Molar Refractivity (cm3/mol) 93.15, Calculated Molar Refractivity
9.3645
Blood brain equilibrium
3.66+/-0.513, clearance across BBB into Brain 44.1+/-5.5mL/100g min,
logD at pH 1, pH 2, pH 3, pH 4, pH 5, pH 6, pH 7, pH 8, pH 9, pH
10 [t =25, for neutral and ionic compounds] 0.56, 0.56, 0.56, 0.56,
0.6, 0.84, 1.56, 2.49, 3.23, 3.34, {3.57}
Course breakdown
Take home assignment (mechanism
question in synthesis of Artemisinin) and
“midterm” week 6 (handout) (50%)
 Videoconferencing assignments (5), weeks
7-11 (25% total)
 Professional project report week 9 (5%)
 Final poster presentation week 12 (20%)
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Aims of marked component
 Midterm
exam- examines lecture
component material
 Videoconferencing – communication,
rationale, comprehension
 Report – communication,
comprehension
 Poster presentation – future work,
innovation
Current enrollment
 Six
students
 3 companies (teams) of two students
 5 chemists, 1 pharmacologist
 Ideal enrollment 12+ of mixed
groups (chemist + pharmacologist +
biochemist)
Acknowledgements
 QCIC
 Dale
Cameron, Dinesh Vyas, Rick
Friesen, Jack Bikker
 Harold Mastalertz, Sheldon Hiebert,
Sheldon Crane
 Angela Lyon, Michael Kuiper
 Caitlin Latimer (SWEP program,
Queen’s University)