Orally active drugs

Kelder et al. [19] have shown that PSA can be used to model oral absorption and brain penetration of drugs that are transported by the transcellular route. A good correlation was found between brain penetration and PSA (n=45, r=0.917). From analyzing a set of 2366 central nervous system (CNS) and non-CNS oral drugs that have reached at least phase 11 clinical trials it was concluded that orally active drugs that are transported passively by the transcellular route should have PSA< 120 Al In addition, different PSA distributions were found for CNS and non-CNS drugs. 

Angiotensin II causes vasoconstriction by direct stimulation of ATj receptors on the vascular smooth muscle. It also enhances release of the neurotransmitter norepinephrine from the sympathetic nerve fibers present in the blood vessels. The vasopressor effects of Ag II may be inhibited pharmacologically in order to decrease TPR and treat hypertension. An important class of orally active drugs is the ACE inhibitors, including captopril and enalopril, which prevent formation of Ag II. More recently, angiotensin receptor antagonists have been developed that act at the vascular smooth muscle. These drugs, which include losartin and valsartan, are also orally active. 

Gan, L.-S. L., Thakker, D. R., Applications of the Caco-2 model in the design and development of orally active drugs elucidation of biochemical and physical barriers posed by the intestinal epithelium, Adv. Drug Deliv. Rev. 1997, 23, 77-98. 

In the current era with widespread problems of poor solubility [4] a compound (drug) with average permeability and a projected clinical potency of 1 mg kg-1 needs a minimum aqueous solubility of 50-100 jug mL-1 to avoid the use of nonstandard solubility fixing formulation technology. The guidelines published by Pfizer s Curatolo on maximum absorbable dose are an excellent guide for the combination of permeability, solubility and potency required in an orally active drug [8],... 

Orally active drugs that are transported passively by the transcellular route can be tailored to brain permeation by decreasing the PSA to less than 60-70 A2. 

Rather surprisingly, a much more specific, orally-active drug of this type has been available for at least 14 years. Largely unrecognized (for lack of detailed study) thymoxamine (XIX, Arlytene, Carlytene, Moxisylyte. Opilon, Sympal)... 

II.f.2.1. Oral hypoglycaemic agents. There are now five groups of orally active drugs available to lower blood glucose in clinical practice (Table 2). These are sulphonylureas, biguanides, alpha-glucosidase inhibitors, thiazolidinediones, and the incretin derivatives. 

Table 2. Orally active drugs effective in type 2 diabetes ...

The calcium entry blockers or calcium channel blockers are a group of orally active drugs that have been approved for use in the treatment of vasospastic and ef-... 

Sunitinib maleate (1, Sutent, SU11248) was discovered by Sugen, which later became part of Pfizer. It is an orally active drug that exhibits potent anti-angiogenic activity through the inhibition of multiple RTKs. Specifically, 1 inhibits vascular... 

Platinum Drug Development - the Pathway to Orally Active Drugs... 

Hexamethonium was the first orally active drug to treat hypertension. Like all agents in this group it blocks sympathetic and parasympathetic systems alike. Severe side effects have rendered them of historical interest only in hypertension therapy. 

Chris Lipinski [1] identified a set of structural features commonly found in orally active drugs. Because most of the features involve the number five, the... 

In an effort to identify an orally active drug, further optimization in the diaryl urea series led to (64), which inhibits I-IL-8 binding to... 

Gan LSL and Thakker DR. Applications of the Caco-2 Model in the Design and Development of Orally Active Drugs Elucidation of Biochemical and Physical Barriers Posed by the Intestinal Epithelium. Adv Drug Del Rev 1997 23 77-98. 

Compound properties required for an orally active drug have not changed in the last decade with respect to developabil-ity, that is, the probability that a compound will succeed to market approval. Considerable hterature supports the sta-bihty over time of the physicochemical properties of an approved drug. For example, the mean MWT of Food and Drag Administration (FDA) approved drugs is stable over 40 years at about 350 Da. Developabihty stands in contrast to... 

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