Article: Fosinopril

Fosinopril
Systematic (IUPAC) name
4-cyclohexyl-1-[2-[(2-methyl-1-propanoyloxy-propoxy)-(4-phenylbutyl)phosphoryl]acetyl] -pyrrolidine-2-carboxylic acid (Diagrams above are fosinopril and fosinoprilat, respectively. Data below refers to fosinopril unless indicated)
Identifiers
CAS number	98048-97-6
ATC code	C09AA09
PubChem	55891
DrugBank	APRD00526
Chemical data
Formula	C30H46NO7P
Mol. weight	563.663 g/mol
Pharmacokinetic data
Bioavailability	~36%
Protein binding	87% (fosinoprilat)
Metabolism	hepatic, GIT mucosa (to fosinoprilat)
Half life	12 hours (fosinoprilat)
Excretion	renal
Therapeutic considerations
Pregnancy cat.	D (Australia)
Legal status	℞ Prescription only
Routes	oral

Fosinopril is an angiotensin converting enzyme (ACE) inhibitor used for the treatment of hypertension and some types of chronic heart failure. Fosinopril is the first and only phosphonate-containing ACE inhibitor marketed. It is marketed by Bristol-Myers Squibb under the trade name Monopril®.

Development

The development of fosinopril started from the observation of the hypotensive effects of phosphoramidon, an extract from the bacterium Streptomyces tanashiensis. Phosphoramidon was found to be a potent inhibitor of ACE. It was speculated that the phosphoramide moiety in the molecule was central to its inhibition of ACE. Further studies found that the phosphoramide moiety served the dual-purpose of interacting with the Zn²⁺ in ACE, as well as mimicking the transition-state of the natural substrate of ACE.

These discoveries led to the attempt to develop a new group of ACE inhibitors which contained the phosphoramide moiety. The initial lead proved to be very potent but unstable at physiological pH. Later compounds would have a phosphonate moiety (being more stable) in place of the phosphoramide. The lessons learnt in the development of enalapril and later ACE inhibitors were applied to the design and eventually fosinoprilat was developed.

Fosinoprilat and Fosinopril

Fosinoprilat proved to have the same problem as enalaprilat and the other carboxylate-containing ACE inhibitors (namely poor oral bioavailability). The solution, fortunately, was very similar - the addition of a hydrophobic side-chain to modulate the ionisation characteristics of the molecule. Thus fosinopril was developed. Fosinopril is administered as a prodrug and is converted in vivo to the active form fosinoprilat.