2-Azabicyclo[3.3.0]octane-3-carboxylic acid

• CAT Number: M010022
• CAS Number: 109428-53-7
• Molecular Formula: C8H13NO2
• Molecular Weight: 155.19
• Purity: ≥95%
• Synonyms: octahydrocyclopenta[b]pyrrole-2-carboxylic acid
• Storage: -20°C
• IUPAC Name: 1,2,3,3a,4,5,6,6a-octahydrocyclopenta[b]pyrrole-2-carboxylic acid
• InChI: InChI=1S/C8H13NO2/c10-8(11)7-4-5-2-1-3-6(5)9-7/h5-7,9H,1-4H2,(H,10,11)
• InChIKey: OQHKEWIEKYQINX-UHFFFAOYSA-N
• SMILES: C1CC2CC(NC2C1)C(=O)O

Reference

[1]. Arzneimittelforschung. 1984;34(10B):1435-47.
Pharmacokinetics and biotransformation of 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S, 5S)-2-azabicyclo [3.3.0]octane-3-carboxylic acid (Hoe 498) in rat, dog and man.
Eckert HG, Badian MJ, Gantz D, Kellner HM, Volz M.
After oral administration, 2 mg/kg in rat and dog, 10 mg in man, of the carbon-14-labeled angiotensin I converting enzyme inhibitor 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S, 5S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498), absorption (rat 56%, dog 43%, man 56%) occurred rapidly and induced maximum blood levels between 0.25 and 1 h. The radioactivity disappeared from the blood in one or two phases with half-lives of 0.6 h in the rat, 1/3.8 h in dog and 0.5/2.9 h in man. Studies in rats have shown that the radioactivity is distributed rapidly to all tissues. Markedly higher concentrations than in the blood were found in the liver, kidneys, and particularly in the lungs. The elimination from the lungs, which showed the highest concentrations until 5 d after administration, occurred with a half-life of 63 h. In rats, 26% of the dose was excreted with the urine and 71% with the feces. About one third of the dose was eliminated with the bile and about 13% was reabsorbed from the bile. The excretion in the breast milk of rats was low. Placental transfer in pregnant rats was low and transient. The radioactivity recovered from the urine of dogs amounted to 15%, that recovered from the feces amounted to 79%. In man, 56% of the radioactivity was excreted with the urine and less than 40% with the feces. Whereas in rat urine one metabolite dominates, the metabolite patterns in urine and serum/plasma of man and dog – which are very much alike – reveal a different biotransformation with three main metabolites. Unchanged Hoe 498, as well as its dicarboxylic acid and other metabolites appear only in low concentrations in this pattern.
PMID: 6097271 [Indexed for MEDLINE]

[2]. Arzneimittelforschung. 1984;34(10B):1417-25.
Cardiovascular and antihypertensive activities of the novel non-sulfhydryl converting enzyme inhibitor 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)-2- azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498).
Schölkens BA, Becker RH, Kaiser J.
The cardiovascular and antihypertensive activities of the novel orally active non-sulfhydryl converting enzyme (CE) inhibitor 2-[N-[(S)-1-Ethoxycarbonyl-3-phenyl-propyl]-L-alanyl] -(1S,3S,5S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498) were evaluated in several experimental preparations. The hemodynamic profile of Hoe 498 in anesthetized animals was characterized by a reduction in systemic blood pressure which was associated with a decrease in total peripheral and renal vascular resistance. These effects were enhanced upon sodium depletion. In conscious normotensive rats a single oral administration of Hoe 498 reduced systemic blood pressure for more than 5 h. The development of acute renovascular hypertension in anesthetized rats was prevented by oral pretreatment with Hoe 498. In conscious rats with renovascular hypertension (two-kidney, one clip) single oral doses of Hoe 498 induced a long lasting antihypertensive effect. Chronic oral treatment of spontaneously hypertensive rats with Hoe 498 lowered arterial blood pressure more effectively than enalapril. The threshold antihypertensive dose for Hoe 498 was 0.01 mg/kg/d, for enalapril 1 mg/kg/d. In conscious hypertensive dogs (two-kidney, two wrapped) Hoe 498 at a single oral dose of 10 mg/kg reduced systemic blood pressure for more than 6 h. Oral administration of Hoe 498 in a dose of 1 mg/kg/d for 5 d normalized systemic blood pressure in conscious hypertensive dogs. These findings demonstrate that in various models of experimental hypertension the novel orally active converting enzyme inhibitor Hoe 498 exerts marked cardiovascular and potent prolonged antihypertensive activities, which merit exploration with respect to possible therapeutic benefits.
PMID: 6097268 [Indexed for MEDLINE]

[3]. Arzneimittelforschung. 1984;34(10B):1448-51.
Tolerance and pharmacodynamics of the angiotensin converting enzyme inhibitor 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)-2- azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498) in healthy volunteers.
Witte PU, Metzger H, Eckert HG, Irmisch R.
In healthy volunteers a single oral dose of 5 mg 2-[N-[(S)-1-Ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S, 5S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498) was well tolerated. Following 5 mg Hoe 498 plasma angiotensin converting enzyme (ACE) activity was inhibited by almost 100% up to 8 h. A marked effect on plasma ACE was observed for more than 8 days. Plasma renin activity increased whereas aldosterone plasma levels decreased only slightly. Sodium and potassium excretion was not influenced by the compound. Systolic and diastolic blood pressure was slightly lowered by Hoe 498, whereas no relevant changes in pulse rate were observed.
PMID: 6097272 [Indexed for MEDLINE]

[4]. Arzneimittelforschung. 1984;34(10B):1399-401.
Synthesis of a highly active angiotensin converting enzyme inhibitor: 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)-2- azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498).
Teetz V, Geiger R, Henning R, Urbach H.
The convergent, diastereoselective synthesis of 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)-2- azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe acid (Hoe 498), a new ACE-inhibitor with improved bioavailability and pharmacokinetics, is described.
PMID: 6097264 [Indexed for MEDLINE]

[5]. Arzneimittelforschung. 1984;34(10B):1402-6.
2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S,5S) -2-azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498)–a new and highly effective angiotensin I converting enzyme inhibitor.
Metzger H, Maier R, Sitter C, Stern HO.
2-[N-[(S)-1-Ethoxycarbonyl-3-phenylpropyl]-L-alanyl] – (1S,3S,5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid (Hoe 498) is a new, very effective and long lasting, nonsulfhydryl angiotensin I converting enzyme inhibitor. Using hip-his-leu as substrate, the IC50-values for Hoe 498 and its diacid derivative were 26 or 4.2 nmol/l, respectively. Hoe 498 acts as a prodrug. It is hydrolyzed by an esterase into its active diacid derivative. Sera contain high esterase activities. In comparison to sera from man, dog and rabbit, rat sera have the highest esterase activity. Hoe 498 or its diacid derivative do not modulate the membrane bound adenylatecyclase system of tissues under investigation. The results are discussed in respect of the regulation of the angiotensin II-synthesis and to the regulation of Ca2+-channels in membranes.
PMID: 6097265 [Indexed for MEDLINE]