Duke University Colloquium in Organic Chemistry Featuring Dr. Michelle Garnsey and Profs. Robert Knowles and David Nagib

Michelle Garnsey (Pfizer)
"Discovery of the MC4R antagonist PF-07258669 as a potential treatment for appetite loss."

The melanocortin-4 receptor (MC4R) is a centrally expressed, Class A GPCR that plays a key role in the regulation of appetite, food intake, and energy expenditure. Deficiencies in MC4R signaling, due to either the loss of receptor function or the loss of production and processing of endogenous agonist peptides, result in hyperphagia, increased linear growth, and increased body mass in humans. Antagonism of MC4R signaling has the potential to mitigate decreased appetite and body weight loss in the setting of anorexia or cachexia due to underlying disease. We will report on the identification of a series of orally bioavailable, small-molecule MC4R antagonists using a focused hit identification effort and the optimization of these antagonists for potency, brain penetration, and ADME attributes leading to the identification of PF-07258669 as a clinical candidate.

Robert Knowles (Princeton University)
"Organic Synthesis Away from Equilibrium"

Inspired by biological photosynthesis and advances in solar fuels chemistry, our lab has become interested in light-driven strategies for organic synthesis wherein excited-state redox events facilitate transformations that are otherwise thermodynamically unfavorable. These electron transfer-based schemes provide a general mechanism for driving reactions in opposition to a thermodynamic gradient by selectively channeling the energy generated from photon-absorption events. Moreover, as these reactions occur across multiple free energy surfaces, they are able to circumvent the constraints of microscopic reversibility that govern thermal processes and enable unique forms of selectivity. Several recent projects will be discussed.

David Nagib (The Ohio State University)
"Harnessing Radicals and Carbenes To Enable Unconventional Reactivity"

Radical and carbene chemistry can afford opposite or orthogonal reactivity to classic two-electron pathways. By developing radical chaperone strategies that merge open (1e-) and closed shell (2e-) processes, we have harnessed this complementary reactivity and imparted new types of chemo-, regio-, and stereo- selectivity for remote, double, or reversed C-H and C-O functionalizations of alcohols, amines, and carbonyls. These radical chaperoning tools are continually being developed to streamline the synthesis of complex, medicinally relevant mole