Roumen Nikolaev Radinov

Discovery of Piragliatin—First Glucokinase Activator Studied in Type 2 Diabetic Patients

Glucokinase (GK) activation as a potential strategy to treat type 2 diabetes (T2D) is well recognized. Compound 1, a glucokinase activator (GKA) lead that we have previously disclosed, caused reversible hepatic lipidosis in repeat-dose toxicology studies. We hypothesized that the hepatic lipidosis was due to the structure-based toxicity and later established that it was due to the formation of a thiourea metabolite, 2. Subsequent SAR studies of 1 led to the identification of a pyrazine-based lead analogue 3, lacking the thiazole moiety. In vivo metabolite identification studies, followed by the independent synthesis and profiling of the cyclopentyl keto- and hydroxyl- metabolites of 3, led to the selection of piragliatin, 4, as the clinical lead. Piragliatin was found to lower pre- and postprandial glucose levels, improve the insulin secretory profile, increase β-cell sensitivity to glucose, and decrease hepatic glucose output in patients with T2D.

SELECTIVE PALLADIUM-CATALYZED HYDROGENOLYSIS OF A SECONDARY PROPARGYLIC ALCOHOL IN THE SYNTHESIS OF VITAMIN D ANALOG RO 23-7553 : SUBSTRATE AND LIGAND CONTROL

Selective palladium-catalyzed hydrogenolysis of propargylic alcohol 9, via its formate 10 or carbonate 13, gave up to 98% of alkyne 11. Alkyneallene selectivity is controlled by the steric bulk of the phosphine ligand, as well as the propargylic (C-22) and alkyne (C-24) substituents in the substrate. A steric ligand-substrate interaction in the intermediate π-propargylallenyl palladium complexes is suggested to explain these effects.

Identification of RO4597014, a Glucokinase Activator Studied in the Clinic for the Treatment of Type 2 Diabetes.

To resolve the metabolite redox cycling associated with our earlier clinical compound 2, we carried out lead optimization of lead molecule 1. Compound 4 showed improved lipophilic ligand efficiency and demonstrated robust glucose lowering in diet-induced obese mice without a liability in predictive preclinical drug safety studies. Thus, it was selected as a clinical candidate and further studied in type 2 diabetic patients. Clinical data suggests no evidence of metabolite cycling, which is consistent with the preclinical profiling of metabolism.

Red-Al® reduction of 4-silyloxy propargylic alcohols. A surprising round trip for the silyl group

Abstract The Red-Al ® reduction of 4-silyloxy propargylic alcohols to 4-silyloxy allylic alcohols involves two consecutive regio- and stereospecific 1,3 silyl migrations — from oxygen to carbon and then back to the original oxygen.