Molecular and Pharmacokinetic Properties of 222 Commercially Available Oral Drugs in Humans.

Abstract

This study was performed to determine the exclusion criteria that differentiate poorly absorbed drugs from good drug candidates, and to accelerate drug development by exclusion of unnecessary assessment. The molecular and pharmacokinetic properties of 222 commercially available oral drugs were tabulated and their correlations were analyzed. The exclusion criteria obtained were 1) a molecular weight of more than 500, and 2) a ClogP value of more than 5. Exceptions to molecular weight criteria were compounds with a sugar moiety, high atomic weight, and large cyclic structure. It was also suggested that being a substrate for MDR1 (P-glycoprotein) does not always result in poor bioavailability, and that drug development by chemical modification of a seed or lead compound with quantitative structure activity relationship analysis can result in lower bioavailability, higher bound fraction and lower urinary excretion, which would hamper later development processes and might result in considerable drug-drug interaction. The criteria should be adjusted according to the pharmacological profiles of the agents in question and depending on the estimated profit, but ignoring these criteria may result in a significant waste of time and money during drug development.

Medicinal chemical properties of successful central nervous system drugs

“…6,58 In general, drugs aimed at the CNS tend to have lower polar surface areas than other classes. 59,60 PSA for CNS drugs is significantly less than for other therapeutics with PSA for CNS penetration estimated at 60 -70 Å 2 through 90 Å 2 . 45, 46 The upper limit for PSA for a molecule to penetrate the brain is around 90 Å 2 .…”

In SilicoADME/Tox Predictions

“…500 and log P ! 5) that differentiated poorly absorbed drugs from good drug candidates after investigation of over 200 marketed oral drugs [107]. Similar investigations were carried out by several other groups [9,60,108] and usually supported the view of Lipinski and collaborators.…”

The Tertiary Amine Nitrogen Atom of Piperazine Sulfonamides as a Novel Determinant of Potent and Selective β3‐Adrenoceptor Agonists

“…A drug with Clog P > 5 is assumed to be poorly absorbed. [25] The target compounds 7 a-d, 12 a,b,e, 15 a-c, 15 e-g, and 20-29 ( Figure 3) were prepared in fair to good yields, and their b 3 -AR activity was determined by measuring cAMP levels (cAMP Biotrak TM GE Healthcare) in CHO-K1 cells expressing human cloned b 3 -AR (Table 1, Figure 4). (R)-(À)-Isoproterenol (ISO) was also tested as a reference compound by using the same method.…”