Loriatinib macrocyclisation

The story of Lorlatinib started with an existing inihibitor and used macrocyclization to improve properties. Macrocyclisation has been a recent approach to improving small molecules, and is usually performed as part of a structure-based design program. The ideal starting point is a high quality x-ray structure determination of the small molecule bound to protein, thats shows the molecule is folded, in such a way, that groups in the molecules are close enough together to ‘join up’, thus forming a large ring. The difference in entropy on the binding can be significant and can yield highly potent compounds. In addition, these macrocycles present different shapes and have been demonstrated to have improved absorption and reduced efflux. Although the approved drug Crizotinib has robust efficacy in ALK-positive tumors, patients eventually develop resistance, and metastases to the brain can occur. Many cancer drugs have poor penetration across the Blood Brain Barrier (BBB), so a new suite of kinase inhibitors with high brain blood concentration is highly desirable. The authors in this paper started from Crizothinib and initially made acyclic compounds, focussing on efficient small molecules (low LipE) to improve brain penetration (see references within).  Co-crystallisation of these inhibitors in ALK showed the compounds were folded in the U-shape, positioning two aryl groups close together (see Figure 3). The idea for macrocyclic compounds was born, but this was not without difficulties. The paper describes in great detail the medicinal chemistry and synthetic chemistry challenges and is rich in data and analysis.


Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations.

J. Med. Chem. 2014, 57, 11, 4720–4744

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