The Therapeutic Potential of Candoxatril, a Neutral Endopeptidase Inhibitor, in Humans

McDowell, Garry; Nicholls, D. P.

doi:10.1111/j.1527-3466.2000.tb00051.x

Cited by 17 publications

(12 citation statements)

References 64 publications

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“…We chose as a starting point the Pfizer-proprietary Candoxatrilat, 1 (9,10). The development of this agent as a treatment for chronic heart failure was discontinued due to poor efficacy, but as this chemotype had proven clinical safety and toleration, we considered 1 an excellent lead for this program.…”

Section: Resultsmentioning

confidence: 99%

The Discovery of Small Molecule Inhibitors of Neutral Endopeptidase. Structure–Activity Studies on Functionalized Glutaramides

Maw¹,

Stobie²,

Planken³

et al. 2005

Chem Biol Drug Des

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A series of small molecule glutaramides were synthesized and evaluated for potency against canine and human neutral endopeptidase using target criteria of molecular weight <400 and log P between 2 and 4.5 to maximize the likelihood of achieving good oral absorption. The structure-activity relationship (SAR) investigations described in this paper led to the identification of an ethyl 1,3,4-thi-adiazole glutaramide which demonstrated good neutral endopeptidase potency, selectivity and excellent oral absorption in the rat. A major cause of female sexual arousal disorder (FSAD) is thought to be decreased genital blood flow which is manifest as reduced vaginal, labial and clitoral engorgement (1-3). Treatment of women with FSAD may be achievable by restoration of the normal sexual arousal response via enhancement of genital blood flow. Vasoactive intestinal peptide (VIP) is one of the principal vasoactive neurotrans-mitters found in the vasculature of the vagina (4,5). Neutral endop-eptidase (NEP, EC3.4.24.11) is a Zn-dependent metallo-endopeptidase (6,7) which is expressed in a range of mammalian tissues including vagina and clitoris, and modulates the activity of a number of bioactive peptides including VIP (8). The aim of the program described in this paper was to investigate the role of NEP in the control of female genital blood flow through the design and synthesis of a series of potent and selective small molecule inhibi-tors of NEP. Results and Discussion We chose as a starting point the Pfizer-proprietary Candoxatrilat, 1 (9,10). The development of this agent as a treatment for chronic heart failure was discontinued due to poor efficacy, but as this chemotype had proven clinical safety and toleration, we considered 1 an excellent lead for this program. Candoxatrilat has essentially no oral absorption as the parent diacid, and variable and incomplete bioavailability as its indanyl ester prodrug (6). We sought an agent of high oral bioavailability which would not require a prodrug for absorption to simplify the potential development of this agent, and therefore sought mono-acid derivatives of 1. This agent should be rapid onset, of short half-life and be entirely suitable for prn (on-demand) dosing. We reasoned that by retaining the Zn-binding acid group of 1, we may be able to remove the second non-Zn binding acid group and retain potent NEP activity and selectivity in compounds of general structure 2. Critical to this strategy was carefully targeting a range of physicochemistry which was most likely to deliver a well absorbed agent with our target pharmacoki-netic profile. In practice, this entailed targeting relatively small compounds of molecular weight <400, and of relatively polar character, with log P between 2 and 4.5. 1 This strategy is outlined in Figure 1. The synthesis of compounds of structure 2 was straightforward. Initial SAR investigations were performed on the n-propyl glutara-mide as a small, low molecular weight P1¢ substituent which was easily installed by facile allyl bromide alkylation of ...

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Section: Resultsmentioning

confidence: 99%

The Discovery of Small Molecule Inhibitors of Neutral Endopeptidase. Structure–Activity Studies on Functionalized Glutaramides

Maw¹,

Stobie²,

Planken³

et al. 2005

Chem Biol Drug Des

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“…Candoxatril is a neutral eudopeptidase (NEP) inhibitor that increases plasma concentrations of atrial natriuretic factor (ANF potentiator) and thereby produces natriuresis, diuresis, and vasorelaxation. [294][295][296] Candoxatril has demonstrated clinical efficacy for the treatment of congestive heart failure (CHF), 297 and therefore it is used for the treatment of a chronic cardiac failure, 298 and a hypertension. 294 300 Highly enantioselective hydrogenation of 197b (X þ ¼ Na þ ) was performed in MeOH under 5 bar H 2 -pressure affording after 1 hour the desired saturated product (S)-198b in >99% ee and high yield (95%), and no trace of isomerization product was observed.…”

Section: Ru-catalyzed Hydrogenation In Drug and Natural Product Synthmentioning

confidence: 99%

“…[294][295][296] Candoxatril has demonstrated clinical efficacy for the treatment of congestive heart failure (CHF), 297 and therefore it is used for the treatment of a chronic cardiac failure, 298 and a hypertension. 294 300 Highly enantioselective hydrogenation of 197b (X þ ¼ Na þ ) was performed in MeOH under 5 bar H 2 -pressure affording after 1 hour the desired saturated product (S)-198b in >99% ee and high yield (95%), and no trace of isomerization product was observed. Two years later (in 2001), Bulliard and co-workers from PPG-Sipsy (Avrill e, France) optimized a Ru-catalyzed hydrogenation of trisubstituted alkene 197 and the whole process was re-evaluated to find a better economic fit.…”

Section: Ru-catalyzed Hydrogenation In Drug and Natural Product Synthmentioning

confidence: 99%

Stereoselective Hydrogenation ofCCBonds: Application to Drug and Natural Product Synthesis

Andrushko

2013

Stereoselective Synthesis of Drugs and Natural Products

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Asymmetric homogeneous hydrogenation is perhaps one of the most researched areas in homogeneous catalysis; thus, it is now used in numerous innovative applications in stereoselective syntheses of many chiral pharmaceutical and natural products. Metal complexes, derived from transition metals, like Rh, Ru, Ir, and so on, and chiral ligands (usually mono‐ or diphosphine ligands), are widely used as catalysts in asymmetric alkene hydrogenation as a result of their efficiency in the preparation of enantiopure compounds with excellent atom economy. This chapter provides many interesting examples of homogeneous enantio‐ and diastereoselective hydrogenation of CC bonds, highlighting the utility of these methods as useful synthetic tools for the construction of stereogenic centers in stereoselective drug and natural product syntheses.

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“…The concept of 'nature's own diuretic' remains an area of research interest. 59 Not surprisingly, in the 21st century, there are examples of molecular genetics starting to impact on the arena of diuretics. A recombinant form of BNP having the same 32 amino acid residue sequence as the endogenous peptide is now available.…”

Section: Miscellaneous Diureticsmentioning

confidence: 99%

Diuretics: a review

Wile

2012

Ann Clin Biochem

118

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Diuretics, in one form or another, have been around for centuries and this review sets out to chart their development and clinical use. Starting with the physiology of the kidney, it progresses to explain how diuretics actually work, via symports on the inside of the renal tubules. The different classes of diuretics are characterized, along with their mode of action. The clinical use of diuretics in conditions like congestive cardiac failure and hypertension, as well as some rarer, but clinically important, conditions is then examined. An account is given of the adverse effects of diuretics and how they come about. Common adverse effects like hypokalaemia and hyponatraemia are examined in some detail, and other electrolyte disturbances like hypomagnesaemia also gain a mention. Diuretic use in chronic kidney disease is examined and new guidelines that have been introduced are presented. A section on diuretic abuse is included as this is becoming an all too common clinical scenario, and the sometimes tragic consequences of this abuse are emphasized. Diuretics also find a role in the diagnosis of forms of renal tubular acidosis and this role is explored. Finally, a selection of some of the newer approaches to diuretic therapy are presented, often the consequence of the increasing development of molecular biology, and some of the novel compounds -which may be in drug formularies of the future -are revealed.

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The Therapeutic Potential of Candoxatril, a Neutral Endopeptidase Inhibitor, in Humans

Cited by 17 publications

References 64 publications

The Discovery of Small Molecule Inhibitors of Neutral Endopeptidase. Structure–Activity Studies on Functionalized Glutaramides

The Discovery of Small Molecule Inhibitors of Neutral Endopeptidase. Structure–Activity Studies on Functionalized Glutaramides

Stereoselective Hydrogenation ofCCBonds: Application to Drug and Natural Product Synthesis

Diuretics: a review

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