The unravelling of the physiological functions of FXR and TGR5 has disclosed unprecedented opportunities for bile acid receptors as drug targets in different therapeutic areas. In the frame of our work in the field aimed at finding novel and potent compounds affecting the bile acid signalling pathways and endowed with tailored metabolic profile and pharmacokinetic properties, we have devised structural modifications of obeticholic acid (OCA also known as 6-ECDCA and INT-747), the 6alpha-ethyl derivative of chenodeoxycholic acid (CDCA) recently approved by FDA for primary biliary cholangitis (PBC) and marketed as Ocaliva. In particular, we found that the replacement of the carboxylic tail with sulfate and sulfonate based side chains of different length greatly affects the properties and biological activity of the resulting compounds. In particular, the presence of a sulfate group at the C23 position increased the potency at both FXR (EC50 0.03 μM) and TGR5 (EC50 0.63 μM) leading to the discovery of 3α,7α,23-trihydroxy-6α-ethyl-24-nor-5β-cholan-23-sulfate (INT-767). INT-767 is currently being evaluated in animal models of diabesity, chronic cholangiopathy and non-alcoholic liver disease (NASH). The importance of INT-767 as the first potent dual FXR/TGR5 agonist with anti-inflammatory and immune-regulatory properties, made the development of a new, more efficient procedure of its preparation of high priority. Indeed, a large amount of INT-767 is needed in order to perform the variety of in vivo assays necessary for advancing the compound in clinical setting of chronic metabolic disorders. In this communication, we report our efforts dedicated to the design and optimization of a new processing method for the large scale preparation of INT-767. In particular, the limitation of previously reported procedures for the synthesis of C23-sulfate bile acid analogues will be analysed and the optimization of single step of the new synthetic approach will be illustrated and discussed.
SCALE-UP SYNTHESIS OF 3α,7α,23-TRIHYDROXY-6α-ETHYL-24-NOR-5β-CHOLAN-23-SULFATE SODIUM SALT (INT-767), A POTENT FXR/TGR5 DUAL AGONIST IN PHASE I CLINICAL STUDIES
GIOIELLO, ANTIMO;
2016
Abstract
The unravelling of the physiological functions of FXR and TGR5 has disclosed unprecedented opportunities for bile acid receptors as drug targets in different therapeutic areas. In the frame of our work in the field aimed at finding novel and potent compounds affecting the bile acid signalling pathways and endowed with tailored metabolic profile and pharmacokinetic properties, we have devised structural modifications of obeticholic acid (OCA also known as 6-ECDCA and INT-747), the 6alpha-ethyl derivative of chenodeoxycholic acid (CDCA) recently approved by FDA for primary biliary cholangitis (PBC) and marketed as Ocaliva. In particular, we found that the replacement of the carboxylic tail with sulfate and sulfonate based side chains of different length greatly affects the properties and biological activity of the resulting compounds. In particular, the presence of a sulfate group at the C23 position increased the potency at both FXR (EC50 0.03 μM) and TGR5 (EC50 0.63 μM) leading to the discovery of 3α,7α,23-trihydroxy-6α-ethyl-24-nor-5β-cholan-23-sulfate (INT-767). INT-767 is currently being evaluated in animal models of diabesity, chronic cholangiopathy and non-alcoholic liver disease (NASH). The importance of INT-767 as the first potent dual FXR/TGR5 agonist with anti-inflammatory and immune-regulatory properties, made the development of a new, more efficient procedure of its preparation of high priority. Indeed, a large amount of INT-767 is needed in order to perform the variety of in vivo assays necessary for advancing the compound in clinical setting of chronic metabolic disorders. In this communication, we report our efforts dedicated to the design and optimization of a new processing method for the large scale preparation of INT-767. In particular, the limitation of previously reported procedures for the synthesis of C23-sulfate bile acid analogues will be analysed and the optimization of single step of the new synthetic approach will be illustrated and discussed.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
