Michael D. Taylor

Comparison of Intestinal Permeabilities Determined in Multiple in Vitro and inSitu Models: Relationship to Absorption in Humans

In vitro and in situ experimental models that are descriptive of drug absorption in vivo are valuable tools in the discovery of new chemical entities that are bioavailable after oral administration. The specific objective of the study was to compare the intestinal permeabilities obtained in the three absorption models for consistency, and to assess the utility of the models in predicting the fraction of dose absorbed in human studies. The intestinal absorption models that were compared are widely used: the rat in situ single-pass intestinal perfusion system, the rat everted intestinal ring method, and monolayers of human colon adenocarcinoma cell line (CACO-2). The models were compared using small molecular reference compounds, as well as a series of peptidomimetic (PM) analogs. Each model had strong potential for estimating the fraction absorbed. For small organic molecules, excellent correlation was observed when permeabilities from CACO-2 cells and perfusions, or everted rings and perfusions, were compared. Weaker correlation was observed between everted rings and CACO-2 cells. Permeabilities for the set of reference compounds and PMs were positively correlated between any two of the three systems. Variance between correlations for reference compounds and PMs are likely due to structural features and physicochemical properties that are unique to the latter class of compounds. The results support caution in extrapolating correlations based on findings with small organic molecules to the behavior of complex peptidomimetics. Corroboration of permeabilities with two methods of determination is a useful cross-validation of experimental systems, as well as producing a reliable permeability assessment. CACO-2 cell monolayers and rat single-pass intestinal perfusion combine the highest correlation between systems, most defined relationship with fraction absorbed in humans, and experimental logistics in-line with discovery candidates.

Improved passive oral drug delivery via prodrugs

Abstract Employing prodrugs to improve drug delivery and oral absorption, in particular, is a proven strategy. This review describes recent examples of prodrugs intended to improve oral delivery through enhanced passive transcellular absorption. The underlying biophysics of passive transcellur transport also is discussed as a framework for prodrug design.

Correlation of adenosine receptor affinities and cardiovascular activity.

Binding affinities of 28 adenosine analogs at A1 adenosine receptors (rat whole brain membranes, [3H]N6-cyclohexyladenosine, CHA), and at A2 adenosine receptors (rat striatal membranes, [3H]NECA) were compared to their EC25 values for decreasing heart rate and increasing coronary flow in the isolated rat heart. Heart rate (an A1 response) correlated with A1 binding affinity (r2 = 0.71, p less than 0.0001) but not with A2 binding affinity (r2 = 0.007, n.s.); conversely, coronary flow (an A2 response) correlated with A2 binding affinity (r2 = 0.83, p less than 0.0001) but not with A1 binding affinity (r2 = 0.05, n.s.). These results confirm that the brain A1 and A2 receptors, studied by binding methods, bear close similarities to their respective counterparts in the heart, studied by means of functional responses.

Adenosine Receptor Agonists. X-Ray Crystal Structure of Neca 1-(6-Amino-9H-Purin-9-Yl)-1-Deoxy-N-Ethyl-β-D-Ribofuranuronamide

Abstract The single crystal x-ray structure of NECA (1-(6-amino-9H-pu-rin-9-yl)-1-deoxy-N-ethyl-β-D-ribofuranuronamide), a 5′-modified adenosine analogue, is reported. Crystallized from methanol as the monohydrate, NECA exists in a syn conformation (sugar syn to purine) in the solid state, consistent with both solution measurements and theoretical calculations. The biological profile of NECA may result from this conformational preference.

Chapter 9 Agents for the Treatment of Congestive Heart Failure

Publisher Summary Insufficient cardiac output initiates compensatory processes involving increased activity of the adrenergic, renin-angiotensin-aldosterone,, prostaglandin, bradykinin, and vasopressin systems. These compensatory mechanisms further decrease peripheral circulation, leading to congestive heart failure (CHF). Even though progress has been made in understanding this disease and developing new therapies, overall mortality has not declined and many unanswered questions remain. The etiology, pathophysiology, and drug treatment of CHF have been the subject of a number of recent reviews. Clearly, the number and diversity of new agents and mechanisms now available or under development is likely to impact favorably on future therapy for CHF. The increase in survival demonstrated in the V-HeFT study is a milestone and other agents, including angiotensin converting enzyme (ACE) inhibitors, are undergoing similar trials. The potential role of the phosphodiesterase (PDE) inhibitor cardiotonics is likely be defined in the near future following the publication of multicenter trials, involving milrinone and enoximone. As a result of this progress, CHF may be better controlled and overall survival may improve. Nonetheless there remains a challenge to discover drug therapies that not only ameliorate symptoms but have a substantive effect on the disease process and progression.

Synthesis of Amino 1,3-Diols. Ring Opening of N-Acyl Activated Lactams with Carbon Nucleophiles

Abstract A synthesis of 6-amino-7-cyclohexyl-3,5-heptanediol 1 (CDH) and related amino 1,3-diols involving a nucleophilic ring opening of N-acyl activated lactams is described. Stereochemical proof of the 1,3-diol moiety is also presented.