Metabolism and Physicochemical Properties

HIGH THROUGHPUT METABOLIC AND PHYSICOCHEMICAL PROPERTY ANALYSIS STRATEGIES AND TACTICS FOR IMPACT ON DRUG DISCOVERY SUCCESS... 

HIGH THROUGHPUT METABOLIC AND PHYSICOCHEMICAL PROPERTY ANALYSIS... 

Two papers described the optimization of LLE and physicochemical properties in a series of pyrazole HTV nonnucleoside reverse transcriptase inhibitors (NNRTIs) and the selection of lersivirine (6) as a development candidate [15,16]. The early lead (7) was relatively lipophilic (clogP = 4.3), rapidly metabolized in human liver microsomes and had an LLE of only 1.9 [pIC50 (HIV RT) - clogP] [15]. An optimization program targeting increased LLE in less lipophilic compounds of low MW (to... 

Building predictive QSAR and QSPR models is a cost-effective way to estimate biological activities, physicochemical properties such as partition coefficients and solubility, and more complicated pharmaceutical endpoints such as metabolic stability and volume of distribution. It seems to be reasonable to assume that structurally similar molecules should behave similarly. That is, similar molecules should have similar biological activities and physicochemical properties. This is the (Q)SAR/(Q)SPR hypothesis. Qualitatively, both molecular interactions and molecular properties are determined by, and therefore are functions of, molecular structures. Or... 

MPTP is also metabolized by other routes involving cytochromes P-450, FAD-dependent monooxygenases, and aldehyde oxidase. However, these seem to be detoxication pathways, as they divert MPTP away from uptake and metabolism in the brain. However, MPTP may inhibit its own metabolism by cytochromes P-450 and thereby reduce one means of detoxication. This example illustrates the importance of structure and physicochemical properties in toxicology. MPTP is sufficiently lipophilic to cross the blood-brain barrier and gain access to the astrocytes. The structure of the metabolite is important for uptake via the dopamine system, hence localizing the compound to a particular type of neuron. Again, uptake into mitochondria is presumably a function of structure, as a specific energy-dependent carrier is involved. 

Capon, B., and Overend, W. G., Constitution and Physicochemical Properties of Carbohydrates, 15, 11-51 Carr, C. Jelleff, and Krantz, John C., Jr., Metabolism of the Sugar Alcohols and Their Derivatives, 1, 175-192 Chizhov, O. S. See Kochetkov, N. K. Churms, Shirley C Gel Chromatography of Carbohydrates, 25, 13-51 Clamp, John R., Hough, L., Hickson, John L., and Whistler, Roy L Lactose, 16, 159-206 Compton, Jack, The Molecular Constitution of Cellulose, 3, 185-228 Conchie, J., Lewy, G. A., and Marsh,... 

Capon, B., and Ovbrend, W. G., Constitution and Physicochemical Properties of Carbohydrates, 16, 11-51 Carr, C. Jellepp, and Krantz, John C., Jr., Metabolism of the Sugar Alcohols and Their Derivatives, 1, 175-192... 

The different enantiomers of optically active compounds have identical chemical and physicochemical properties, except their different influence on the rotation of polarized light. However, a binding site is a chiral environment that discriminates between the different enantiomers as if they were completely different molecules optical enantiomers also differ in their metabolism. Thus, stereochemistry plays an important role in the biological activity of drugs. 

---