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

Abstract

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.

BF3·SMe2 for Thiomethylation, Nitro Reduction and Tandem Reduction/SMe Insertion of Nitrogen Heterocycles

“…5‐(Methylthio)pyrazin‐2‐amine (2j): yellow solid (10.8 mg, 15 %). 1 H NMR (400 MHz, CDCl 3 ) δ 2.51 (s, 3H, SC H 3 ), 4.27 (bs, 2H, N H 2 ), 7.93 (d, J = 1.6 Hz, 1H, Ar H ), 7.96 (d, J = 1.6 Hz, 1H, Ar H ).…”

Conversion of 3,3,3-Trisubstituted Prop-1-ynes with tert-Butylhydrazine into 3,3,3-Trisubstituted Propionitriles Catalyzed by TpRh(C2H4)2/P(2-furyl)3

“…Compounds 1b , 1e , 1g , 1m , 1o , and 1q were prepared as described below. Compounds 1c , 1d , 1k , 1l , and 1p , were prepared following procedures described in the literature. tert -Butylhydrazine was obtained by treatment of tert -butylhydrazine hydrochloride with powdered KOH and subsequent double distillation of the resulting liquid, the last of which was done over CaH 2 .…”

A comprehensive review on glucokinase activators: Promising agents for the treatment of Type 2 diabetes

“…Qian et al carried out the optimization of one of their lead compounds 81 with the lipophilic ligand efficiency (LLE) 4.0 (Qian et al, 2013) that led to the identification of 82 (Figure 7) with the LLE of 5.6. Diol fragment of 82 (RO4597014) provided different molecular properties and improved GK activation efficacy.…”