ROS1 Fusion Inhibitor NVL-520 with MGAT2 Inhibitor BMS-963272
Product Manager：Nick Wilde
1.NVL-520
NVL-520 (CAS: 2739829-00-4) is a selective inhibitor targeting ROS1 fusion and secondary resistance mutations with both TRK-protective properties and good brain penetrance. It is rationally designed to be more than 50-fold selective for ROS1 in 98% of the kinome through a macrocyclic structure.
1.1 Design and structure of NVL-520
NVL-520 is a macrocyclic small molecule compound (see Figure 1A). Computational modeling showed that NVL-520 binds to ROS1 in a manner similar to that of lorlatinib.The aminopyridine moiety in NVL-520 forms two hydrogen bonds with Glu2027 and Met2029 in the hinge region (see Figure 1B).
Figure 1. Design and biochemical activity of NVL-520
The preclinical properties of NVL-520 include potent targeting of ROS1 and its multiple resistance mutations, as well as a high degree of selectivity for ROS1 G2032R over TRK. in addition, it has good brain penetrance. These properties mark the development of a unique ROS1 tyrosine kinase inhibitor that has the potential to overcome the limitations of an earlier generation of tyrosine kinase inhibitors in the treatment of ROS1 fusion-positive patients.
1.2 Synthesis route of NVL-520
A key step in the synthesis of NVL-520 is the synthesis of Intermediate 6 (CAS No. 2921961-52-4), which has the structure 4-[(1-ethyl-1H-pyrazol-4-yl)methyl]-5-iodo-2-methyl-2H-1,2,3-triazole.
Synthesis of (S)-5-fluoro-3-methylbenzo[c][1,2]oxaborinan-1(3H)-ol:
Synthesis of the target product NVL-520:
2.BMS-963272
Recently, researchers have identified a highly potent and selective MGAT2 inhibitor, BMS-963272 (CAS No. 1441057-15-3). As a preferred clinical candidate, this drug has been evaluated in Phase I clinical trials.BMS-963272 is able to achieve targeted and effective exposure in humans at a low dose and can be used to treat metabolic diseases.
Upon further testing in mouse models, the selected analogs were found to significantly reduce food intake and body weight in mice. Subsequent studies of lead drug candidate 12 (BMS-986172) in MGAT2 knockout mice demonstrated targeted and mechanism-based pharmacological effects.
2.1 Synthesis route of BMS-963272
A stereoselective method for the synthesis of the essential (S)-β-sulfinamides 19-20 was developed using Ellman chemistry (Scheme 1) and the absolute stereochemistry at C6 was determined by X-ray analysis of related analogs.
Under alkaline conditions, 1-(1-(cyclopropylmethyl)-1H-pyrazol-3-yl)ethanone 26 underwent alkylation with (bromomethyl)cyclopropane to synthesize 1-(1-(cyclopropylmethyl)-1H-pyrazol-3-yl)ethanone 27.Most of the heterocyclic acetic acids required for the synthesis of the target analogs were readily available. The synthesis of tetrazolone acetic acids 30a-b is detailed in Scheme 2.
For the tetrazolone analogs 12-14 in Scheme 3, the ketoamides 47-49 can be generated using PMB and SEM-protecting acids 30a and 30b. After cyclization, an additional deprotection step (using CAN to deprotect the PMB, and TFA to deprotect the SEM) can be used to generate 12-14 in modest yields.
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Reference
1. Alexander Drilon. et al. NVL-520 Is a Selective, TRK-Sparing, and Brain-Penetrant Inhibitor of ROS1 Fusions and Secondary Resistance Mutations. Cancer Discov (2023) 13 (3): 598-615. https://doi.org/10.1158/2159-8290.CD-22-0968
2.Wei Meng，Robert Brigance. et al. Discovery of 12 (BMS-986172) as a Highly Potent MGAT2 Inhibitor that Achieved Targeted Efficacious Exposures at a Low Human Dose for the Treatment of Metabolic Disorders. J. Med. Chem. 2023, 66, 18, 13135–13147. https://doi.org/10.1021/acs.jmedchem.3c01147