Development and Clinical Application of Phosphorus-Containing Drugs

Abstract

Phosphorus-containing drugs belong to an important class of therapeutic agents and are widely applied in daily clinical practices. Structurally, the phosphorus-containing drugs can be classified into phosphotriesters, phosphonates, phosphinates, phosphine oxides, phosphoric amides, bisphosphonates, phosphoric anhydrides, and others; functionally, they are often designed as prodrugs with improved selectivity and bioavailability, reduced side effects and toxicity, or biomolecule analogues with endogenous materials and antagonistic endoenzyme supplements. This review summarized the phosphorus-containing drugs currently on the market as well as a few promising molecules at clinical studies, with particular emphasis on their structural features, biological mechanism, and indications.

Keywords: Drug modification; Phosphite, phosphate; Phosphorus-containing drugs; Prodrugs.

Fig. 1

Time line of main phosphomonoester and phosphodiester drugs.

Fig. 2

Interconversion of phosphomonoesters prodrugs into their hydroxyl parent drugs and inorganic phosphate during the absorption and distribution process.

Fig. 3

Structures of secondary and tertiary alcohol-derived phosphomonoester drugs 2–4.

Fig. 4

Structures of primary alcohol-derived phosphomonoester drugs 5–13.

Fig. 5

Structures of phenol-derived phosphomonoester drugs 15-17.

Fig. 6

Structures of steroid hormone-derived sodium phosphate drugs 18–22.

Fig. 7

Structures of sodium and calcium phosphate drugs 23-30.

Fig. 8

Structures of phosphodiester drugs 31-34 and cyclic phosphodiester drugs 35-37.

Fig. 9

Time line of main phosphoric amide drugs.

Fig. 10

Structures of phosphoromonoamidate drugs 38–43.

Fig. 11

Structures of phosphorodiamidate 44–47.

Fig. 12

Structures of phosphorotriamidate 48–55.

Fig. 13

Structures of tenofovir slafenamide fumarate 56.

Fig. 14

Time line of main phosphonate, phosphinate, phosphine oxide and other drugs.

Fig. 15

Structures of phosphonate drugs 57–60.

Fig. 16

Structures of antiviral phosphonate drugs 61–63.

Fig. 17

Structures of phosphonate drugs and bioactive molecules 64–68.

Fig. 18

Structures of phosphinate and phosphine oxide drugs 69–73.

Fig. 19

Structures of phosphorofluoridate drug 74 and phosphorothiate drugs 75–76.

Fig. 20

Time line of bisphosphonate and phosphoric anhydrides drugs

Fig. 21

Structures of non-nitrogenous bisphosphonate drugs 77–80.

Fig. 22

Structures of nitrogenous bisphosphonate drugs 81–87.

Fig. 23

Structures of nitrogenous bisphosphonate drugs 88–90.

Fig. 24

Structures of pyrophosphate drugs 91–93.

Fig. 25

Structures of nucleoside pyrophosphate drugs 94-98.

Fig. 26

Structures of other phosphate drugs 99–101.