Jeff McGilvra, Ph.D.

Senior Scientist

Jeff is a Scientist in Cedarburg Hauser Pharmaceuticals' research and development group.  Jeff applies his synthetic chemistry expertise on many different types of projects for our clients including neuromuscular blocker process development chemistry, amino acid functionalization, Suzuki coupling optimization, sulfonamide chemistry, steroid synthesis, process impurity identification and impurity standard generation.

Education

• Applied a synthetic chiral TADDOL derivative for the highly enantio- and diastereoselective hydrogen bond catalyzed Mukaiyama aldol reactions of N,O-ketene acetals
• Developed a 3-stannyl-1-aminodiene for highly enantioselective salen-catalyzed Diels-Alder reactions of acroleins
• Prepared a library of chiral aryl-substituted salen catalysts for use in enantioselective Diels-Alder reactions
• Prepared phomactin C intermediates for testing in platelet activating factor antagonist assays.

• Synthesis of (±)-2-bromo-3-t-butoxypropanoic acid as a model for developing chiral shift NMR spectroscopy methodology. 
• Prepared TDP-cinerulose A via multi-step synthesis for use as an authentic standard.

Background:The ultra–short-acting neuromuscular blocker gantacurium is chemically degraded in vitro by rapid adduction of L-cysteine to its central olefinic double bond. Preliminary data have suggested that exogenous (intravenous) L-cysteine abolishes gantacurium blockade. Two new analogues of gantacurium (CW 002 and CW 011) have been synthesized to undergo slower L-cysteine adduction, yielding intermediate duration. L-Cysteine adduction to and antagonism of these novel agents is further defined herein.

Methods: Comparative reaction half-time for L-cysteine adduction in vitro of the three compounds was determined by high-performance liquid chromatography. ED95 for twitch inhibition in monkeys under isoflurane was calculated, and duration at ~4–5 x ED95 was correlated with reaction half-time for adduction. Speed of L-cysteine antagonism was contrasted with anticholinesterases reversal. Potencies ofCW002 and its adduction product were compared to provide a basis for L-cysteine antagonism.

Results: Rate of L-cysteine adduction in vitro (reaction half-time) was 11.4 and 13.7 min for CW 002 and CW 011 versus 0.2 min for gantacurium, and was inversely related to duration of block (P _ 0.0001). CW 002 and CW 011 were 3_ longer acting than gantacurium (28.1 and 33.3 min vs. 10.4 min), but only half the duration of cisatracurium. The adduct of CW 002 was _70_ less potent than CW 002. L-Cysteine (10 –50 mg/kg intravenously) given 1 min after approximately 4 –5_ ED95 doses of all the three compounds abolished block within2–3 min.

Conclusions: L-Cysteine adduction occurs at different rates by design in olefinic isoquinolinium diester neuromuscular blockers, yielding corresponding durations of action. Antagonism by exogenous L-cysteine is superior to anticholinesterases, inducing inactivation of the active molecules to restore function rapidly at any time.