FDA-approved drugs featuring macrocycles or medium-sized rings

Abstract

Macrocycles or medium-sized rings offer diverse functionality and stereochemical complexity in a well-organized ring structure, allowing them to fulfill various biochemical functions, resulting in high affinity and selectivity for protein targets, while preserving sufficient bioavailability to reach intracellular compartments. These features have made macrocycles attractive candidates in organic synthesis and drug discovery. Since the 20th century, more than three-score macrocyclic drugs, including radiopharmaceuticals, have been approved by the US Food and Drug Administration (FDA) for treating bacterial and viral infections, cancer, obesity, immunosuppression, inflammatory, and neurological disorders, managing cardiovascular diseases, diabetes, and more. This review presents 17 FDA-approved macrocyclic drugs during the past 5 years, highlighting their importance and critical role in modern therapeutics, and the innovative synthetic approaches for the construction of these macrocycles.

Keywords: FDA‐approved drugs; asymmetric synthesis; drug design and development; macrocyclic drugs; peptides and proteins.

Figure 1

Drugs containing cyclic metal complexes.

Figure 2

Drugs containing cyclic peptides.

Figure 3

Drugs containing other cyclic units.

Scheme 1

Synthesis of DOTA‐TATE peptide and ¹⁷⁷Lu DOTA‐TATE (1).

Scheme 2

⁶⁴Cu DOTA‐TATE (2).

Scheme 3

Synthesis of PSMA‐617 and Lutetium Lu 177 vipivotide tetraxetan (3).

Scheme 4

Synthesis of gadopiclenol (4).

Scheme 5

Synthesis of rhPSMA‐7 and flotufolastat F 18 (5).

Scheme 6

Synthesis of lurbinectedin (6).

Scheme 7

Synthesis of setmelanotide (7).

Scheme 8

Synthesis of voclosporin (8).

Scheme 9

Synthesis of terlipressin (9).

Scheme 10

Synthesis of rezafungin (10).

Scheme 11

Synthesis of lorlatinib (11).

Scheme 12

Semi‐chemical synthesis pathway of moxidectin (12) starting from nemadectin (93).

Scheme 13

Biosynthetical route of rifamycin (13).

Scheme 14

Synthesis of lefamulin (14).

Scheme 15

Synthesis of pacritinib (15).

Scheme 16

Synthesis of clarithromycin (16).

Scheme 17

Synthesis of repotrectinib (17).