Effective partnering of academic and physician scientists with the pharmaceutical drug development industry.

This manuscript briefly addresses the drug discovery and development process. It is a long road from the formulation of a good discovery idea to the acceptance of a new drug in the marketplace, and there are many challenges faced along the way to the patient. Collaborations and partnerships are an important part of this process. There are a variety of partnering opportunities, ranging from the discovery of novel technologies and drug targets to lead discovery, compound gifts, and external sourcing. These partnerships help increase confidence and improve decision making on issues of safety and efficacy preclinically, which can reduce attrition and expedite the provision of new quality drugs to patients more quickly and at lower costs. Collaborations involve addressing multiple issues that include infrastructure, safety, regulatory matters, intellectual property, technical and personnel considerations, source document capture and data analysis issues, and legal and strategic alliances. A number of success factors are identified as important for quality collaborations in the drug development process.

Informed toxicity assessment in drug discovery: systems-based toxicology.

Technological advances in the biological, chemical and in silico sciences have transformed many scientific disciplines, including toxicology. A vast new palate of toxicity testing tools is now available to investigators, enabling the generation of enormous amounts of data using only small amounts of test sample and at relatively low cost. In addition to these tools, the pharmaceutical industry has an urgent need for toxicity testing earlier in the process, based on the recognition that safety issues are the single largest cause of drug candidate attrition from development portfolios and the marketplace. However, along with the opportunity provided by new testing tools comes the dilemma of deciding which tools to use and, equally as important, when and why to use them. It may well be unwise to apply a new toxicity test or screening system simply because one can, as both false positive and false negative outcomes can quickly negate the value of a toxicity test system and may even have a net negative impact on drug discovery productivity. This can be true even of test systems that are considered to be 'validated' in the traditional sense. How then is an investigator or drug discovery organization to decide which of the new tools to use, and when to use them? Proposed herein is a strategy for identifying high-value toxicity testing systems and strategies based on program knowledge and informed decision-making. The decision to apply a certain toxicity testing system in this strategy is informed by knowledge of the pharmacological target, the chemical features of molecules active at the pharmacological target, and existing public domain or institutional learning. This 'fit-for-purpose' approach limits non-targeted or 'uninformed' toxicity screening to only those few test systems with high specificity, strong outcome concordance and molecular relevance to frequently encountered toxicity risks (eg, genotoxicity). Additional toxicity testing and screening is then conducted to address specific known or potential toxicity risks, based on existing knowledge of the target pharmacology and secondary pharmacology or chemical attributes with known or suspect risk, and by active 'interrogation' of both the target and active chemical moieties during the drug discovery process. This model for toxicity testing decision-making is illustrated by two case studies from recent experience.

The synthesis of highly potent, selective, and water-soluble agonists at the human adenosine A3 receptor.

Using a combination of parallel and directed synthesis, the discovery of a highly potent and selective series of adenosine A3 agonists was achieved. High aqueous solubility, required for the intended parenteral route of administration, was achieved by the presence of one or two basic amine functional groups.

3'-Aminoadenosine-5'-uronamides: discovery of the first highly selective agonist at the human adenosine A3 receptor.

Selective adenosine A(3) agonists have potential utility for the prevention of perioperative myocardial ischemic injury. Herein, we report on the discovery and synthesis of compound 7. This amino nucleoside agonist possesses unprecedented levels of selectivity for the human adenosine A(3) receptor.

Zoniporide: a potent and highly selective inhibitor of human Na(+)/H(+) exchanger-1.

We evaluated the in vitro pharmacological profile of a novel, potent and highly selective Na(+)/H(+) exchanger-1 (NHE-1) inhibitor, [1-(Quinolin-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine hydrochloride monohydrate (zoniporide or CP-597,396). The potency and selectivity of zoniporide were determined via inhibition of 22Na(+) uptake by PS-120 fibroblast cell lines overexpressing human NHE-1, -2 or rat NHE-3. Additionally, potency for endogenous NHE-1 was confirmed via ex vivo human platelet swelling assay (PSA), in which platelet swelling was induced by exposure to sodium propionate. The pharmacological profile of zoniporide was compared with that of eniporide and cariporide. Zoniporide inhibited 22Na(+) uptake in fibroblasts expressing human NHE-1 in a concentration-dependent manner (IC(50) = 14 nM) and was highly selective (157-fold and 15,700-fold vs. human NHE-2 and rat NHE-3, respectively). Zoniporide was 1.64- to 2.6-fold more potent at human NHE-1 than either eniporide or cariporide (IC(50) = 23 and 36 nM, respectively). Zoniporide was also more selective at inhibiting human NHE-1 vs. human NHE-2 than either eniporide or cariporide (157-fold selective compared with 27- and 49-fold, respectively). All three compounds inhibited human platelet swelling with IC(50) values in low nanomolar range. From these results, we conclude that zoniporide represents a novel, potent and highly selective NHE-1 inhibitor.