John Kenneth White

Identification of a metabolically stable triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with antimalarial activity in mice.

Plasmodium falciparum causes 1-2 million deaths annually. Yet current drug therapies are compromised by resistance. We previously described potent and selective triazolopyrimidine-based inhibitors of P. falciparum dihydroorotate dehydrogenase (PfDHODH) that inhibited parasite growth in vitro; however, they showed no activity in vivo. Here we show that lack of efficacy against P. berghei in mice resulted from a combination of poor plasma exposure and reduced potency against P. berghei DHODH. For compounds containing naphthyl (DSM1) or anthracenyl (DSM2), plasma exposure was reduced upon repeated dosing. Phenyl-substituted triazolopyrimidines were synthesized leading to identification of analogs with low predicted metabolism in human liver microsomes and which showed prolonged exposure in mice. Compound 21 (DSM74), containing p-trifluoromethylphenyl, suppressed growth of P. berghei in mice after oral administration. This study provides the first proof of concept that DHODH inhibitors can suppress Plasmodium growth in vivo, validating DHODH as a new target for antimalarial chemotherapy.

Lead-optimization of aryl and aralkyl amine based triazolopyrimidine inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase with antimalarial activity in mice

Malaria is one of the leading causes of severe infectious disease worldwide; yet, our ability to maintain effective therapy to combat the illness is continually challenged by the emergence of drug resistance. We previously reported identification of a new class of triazolopyrimidine-based Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors with antimalarial activity, leading to the discovery of a new lead series and novel target for drug development. Active compounds from the series contained a triazolopyrimidine ring attached to an aromatic group through a bridging nitrogen atom. Herein, we describe systematic efforts to optimize the aromatic functionality with the goal of improving potency and in vivo properties of compounds from the series. These studies led to the identification of two new substituted aniline moieties (4-SF(5)-Ph and 3,5-Di-F-4-CF(3)-Ph), which, when coupled to the triazolopyrimidine ring, showed good plasma exposure and better efficacy in the Plasmodium berghei mouse model of the disease than previously reported compounds from the series.

Donald Trump and the Scourge of Populism

Populism is a means of speaking to voters, a mode of speech that Michael Kazin once called “the populist persuasion.” During times of economic stress and cultural change, populism often becomes a popular means of communication, and has been used by aspirants for the presidency ranging from William Jennings Bryan to Bernie Sanders and Donald Trump. It is particularly potent when conditions exist that refute historian John Crozier’s description of the American polity as resting on a “gently graded prosperity.” The lack of any “gently graded prosperity” in 2016 fueled the candidacies of Bernie Sanders and Donald Trump. This article focuses on Trump, noting his penchant for action, not adherence to conservative principles or Republican party orthodoxy. The “scourge” Donald Trump’s populism, like his predecessors is that he blames the “other” for the failures of American government and the inability of those who aspire to achieve the American Dream from achieving their goals. This is the scourge of populist candidates who have led their respective parties to ultimate defeat and repudiation. In Trump’s case, blaming Hispanics and immigrants for the country’s problems is a scourge that will take the Republican party years to recover from once the 2016 election is over and the ballots counted.

E. E. Schattschneider and the Responsible Party Model

Shortly before his death in 1971 E. E. Schattschneider said, “I suppose the most important thing I have done in my field is that I have talked longer and harder and more persistently and enthusiastically about political parties than anyone else alive.” Schattschneiders claim is not boastful, but factual. Exactly fifty years ago he completed Party Government , a book that remains a “must” read for students of the U.S. party system. But Schattschneider did more than write books. As Chairman of the APSA-sanctioned Committee on Political Parties, he presided over a debate that resulted in the seminal report, Toward a More Responsible Two-Party System . Like Party Government , this also is a “must” read. Evron Kirkpatrick proclaimed it “a landmark in the history of political science as policy science” (1971). Clinton Rossiter said he would “recommend it … to all who are interested in moving toward stronger party government” (1960). Theodore J. Lowi ranked the Schattschneider committee report as “second only to the 1937 Presidents Committee on Administrative Management as a contribution by academics to public discourse on the fundamentals of American democracy” (1985). William Crotty believed it exercised “the most significant influence on the debate over the operation of political parties that occurred between the Progressive period and the party reform movement of the 1970s” (1980). The responsible party model has had a long life in part because of the passionate arguments Schattschneider made on its behalf.

How Should Political Science Judge Ronald Reagan

Was Ronald Reagan a great President? How do we know? This essay examines the standards of presidential greatness used by historians and political scientists over the years, measuring Reagans presidency against them and them against the Reagan presidency.

The Foreign Policy Election That Wasn’t

The 2008 presidential election was supposed to be all about Iraq; it was not. It was supposed to be about Afghanistan; it was not. It was supposed to be about terrorism; it was not. It was supposed to be about foreign policy; it was not. In fact, the 2008 election was eerily reminiscent of the Great Depressiondominated election of 1932 that saw Franklin D. Roosevelt’s ascension to the White House. The financial crisis that blossomed in October 2008 served to seal John McCain’s fate in a year when voters were already tired of the Republicans and were eager to dispatch George W. Bush to Texas. That month, the Dow Jones Industrial Average experienced a massive 6,000-point fall from its 14,000-peak a year earlier. More than 8 trillion dollars in stock value was lost in just a few short weeks. On a single day, October 10, 2008, the stock market had a 1,000-point swing, a first. And in the ensuing days, the market was extremely jittery—rising 900 points one day; losing 700 points the next. To insure financial stability, George W. Bush proposed a massive

A Campaign to Remember

700 billion Wall Street rescue plan—the largest government intervention in the private markets since Franklin D. Roosevelt’s National Recovery Administration efforts of the 1930s.

Populism in the United States

It was the primary campaign of a century—or, at least, the last half century. Not since 1952 had there been a contest in which either an incumbent president or vice president had not sought their party’s presidential nomination.

A Review of “Why Iowa? How Caucuses and Sequential Elections Improve the Presidential Nominating Process”

In the United States, populism has made brief but important appearances throughout history. Populism has a particular appeal to Americans, as the ideas of popular sovereignty and equality of opportunity are highly valued. Whenever inequality becomes a dominant issue or when a class of people is viewed as getting “something for nothing,” populism can enjoy success at the polls. Throughout history, populism’s appeal has been toward the makers of US society, while the takers are those who are viewed as abusing the system. But the history of US populism is a checkered one. As populism gains ascendancy, assertions over who is to blame for the country’s problems often degenerates into name-calling and race-baited politics that signal populism’s inevitable decline. Donald Trump is the latest manifestation of populism’s political impulses. His rise to the presidency was fuelled by the grievances of blue-collar workers over stagnant wages, a rising immigrant population, and a feeling that elites in Washington, D.C., were not looking out for their interests. That being said, his deeply troubled presidency provides a strong hint that the manifestation of populism in American politics is, once more, headed toward an inevitable historical ebb.

Catholics and the Politics of Change: The Presidential Campaigns of Two JFKs

and that the hundreds of billions lent to banks under the TARP program had been lost (despite reports that nearly all the funds would be recovered and some elements of TARP would show a profit)” (162). There is a promising research question here, on the extent to which such misimpressions were due to presidential ineptness or to an extraordinarily harsh environment for shaping public opinion from the White House. The evidence compels us to ask: Is the pulpit still bully? Second, several of the authors offer some variation on the theme that crisis empowers the president (73, 89, 117)—thus, at least by implication, heightening the magnitude of the administration’s shortcomings by suggesting that the 2008 financial crisis opened the way for a transformational presidency that did not come. Yet perhaps it is the case that not all crises are equal. As Joseph White hints (184), given the timing of the financial collapse within the fixed political calendar, Obama inherited a situation that looked more like 1930 than 1933. That contention leads to the disquieting prospect that Obama’s political time resembles more closely Herbert Hoover’s than FDR’s.