Structure-Activity Relationships. Drug Design. Barbiturates - . pharmacological and structural class. usually administered as salts. Modifications. Uses: sedative hypnotic antianxiety. An Antiischemic, Bradycardic Therapeutic Agent. bradycardia - slowed heartbeat.
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pharmacological and structural class
usually administered as salts
bradycardia - slowed heartbeat
ischemia - condition in which the heart is deprived of oxygen and toxic metabolites cannot be removed.
[Ca2+] very low in the cytosol.
Ca2+-channels allow movement of calcium ions away from myosin to control muscle contraction.
This drug would slow down the heart rate in order to decrease the oxygen demand. However, it is not desirable to lower the contractile force. Existing calcium-channel blocking drugs, while inducing bradycardia, also decrease the contractile force. This can lead to congestive heart failure.
reduce heart rate, maintain contractile force, increase duration of action
Therapeutic goals -
Lipinski’s Rule of 5 - a drug candidate will not be a good candidate
for oral bioavailability if:
postdoc Cal Tech
Christopher Lipinski (Pfizer)
screened >2300 compounds to develop the four characteristics
quickly adopted by pharmaceutical companies for early ADME
E.B. Hersherg Award for Important Discoveries in Medicinally Active Substances(2004); 2004 ACS Division of Medicinal Chemistry Award
Fragments of Active Structures (FAST®) - SGX Pharmaceuticals
Developed a library of small molecules (fragments)
used to produce lead compounds.
1400 fragments - 140 shape-diverse pools
active sites, allosteric sites, new(novel) sites
X-ray crystallography (binding)
Enthalpy Array (H of ligand binding)
SPR -plasmon resonance (kinetics of ligand binding)
Scripps PARC Institute
enthalpy of ligand binding
Improvements in IC50 and EC50
(quantitative structure-activity relationship)
(quantitative structure-property relationship)
enantiomer of X
Formulations, Durability, Optical Isomerism
A,F –hydrogen bond donors
B,E– hydrogen bond acceptors
C– hydrophobic group