ABSTRACT
Compound 4 (PF-04971729) belongs to a new class of potent and selective sodium-dependent glucose cotransporter 2 inhibitors incorporating a unique dioxa-bicyclo[3.2.1]octane (bridged ketal) ring system. In this paper we present the design, synthesis, preclinical evaluation, and human dose predictions related to 4. This compound demonstrated robust urinary glucose excretion in rats and an excellent preclinical safety profile. It is currently in phase 2 clinical trials and is being evaluated for the treatment of type 2 diabetes.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Drug Discovery , Sodium-Glucose Transporter 2 Inhibitors , Animals , Area Under Curve , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Crystallography, X-Ray , Drug Evaluation, Preclinical , Humans , Magnetic Resonance Spectroscopy , Mass Spectrometry , Models, Molecular , RatsABSTRACT
A synthetic approach to the hyperevolutin A acylated phloroglucinol ring system is described. Thus, intramolecular allene-nitrile oxide cycloaddition of 10 was used to construct the bicyclic framework and vicinal quaternary centers in cycloadduct 20 in the key bond-forming step. Treatment of 20 with Raney nickel and hydrogen gas produced primary enamine 21 which contains a nonenolizable beta,beta-tricarbonyl group in latent form.