Non-peptidic inhibitors of neutral endopeptidase 24.11 1. Discovery and optimization of potency

Lombaert, Stéphane De; Blanchard, Louis; Tan, Jenny; Sakane, Yumi; Berry, Carol; Ghai, Rajendra D.

doi:10.1016/0960-894x(94)00474-t

Cited by 65 publications

(36 citation statements)

References 15 publications

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“…The improvement in NEP inhibition was very slight when compared with 3 ( Table 1), showing that the free amino group was not detrimental for NEP recognition and that the side chains selected to interact with the S 1 , S 1 Ј, and S 2 Ј subsites of NEP were not optimized. It has been shown that a biphenyl group in the P 1 Ј position significantly increases NEP inhibition (31). However, it also has been shown that an accumulation of aromatic or aliphatic bulky side chains in a pseudotripeptide is unfavorable for NEP binding (32).…”

Section: Discussionmentioning

confidence: 99%

Aminophosphinic inhibitors as transition state analogues of enkephalin-degrading enzymes: A class of central analgesics

Chen

Noble

Coric

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

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Inhibition of aminopeptidase N and neutral endopeptidase-24.11, two zinc metallopeptidases involved in the inactivation of the opioid peptides enkephalins, produces potent physiological analgesic responses, without major sideeffects, in all animal models of pain in which morphine is active. Dual inhibitors of both enzymes could fill the gap between opioid analgesics and antalgics. Until now, attempts to find a compound with high affinity both for neutral endopeptidase and aminopeptidase N have failed. We report here the design of dual competitive inhibitors of both enzymes with K I values in the nanomolar range. These have been obtained by selecting R 1 , R 2, and R 3 determinants in aminophosphinic-containing inhibitors: NH 2 OCH(R 1 )P(O)O (OH)CH 2 OCH(R 2 )CONHOCH(R 3 )COOH, for optimal recognition of the two enkephalin inactivating enzymes, whose active site peculiarities, determined by site-directed mutagenesis, have been taken into account. The best inhibitors were 10؋ more potent than described dual inhibitors in alleviating acute and inf lammatory nociceptive stimuli in mice, thus providing a basis for the development of a family of analgesics devoid of opioid side effects.Acute and chronic pain are incapacitating diseases, and an improvement in their management is a high priority. Two classes of pain-alleviating substances currently are used in clinic. The first one is constituted by morphine and surrogates, which are the most potent and useful compounds to reduce severe pain, including pain associated with terminal issues. Antalgics including aspirin, paracetamol, and related substances provide the second group. These compounds inhibit the formation of hyperalgesic substances such as prostaglandins and are efficient in reducing inflammatory pain. However, there is a need for compounds capable of filling the gap between opioids and antalgics, which could be used for the treatment of postoperative, osteoarticular, and neuropathic pain as well as pain in children and in the elderly.One of the most promising avenues in the search for such compounds is to improve the potency of the physiological system of pain control (1), constituted by the endogenous opioid peptides, enkephalins which interact with two specific binding sites, the and the ␦ receptors, strategically located at various levels of nociceptive pathways (2). This can be realized by inhibition of the membrane-bound zinc metallopeptidases involved in the rapid inactivation of the enkephalins. One of these enzymes is neutral endopeptidase-24.11 (NEP, neprilysin, EC 3.4.24.11) and other one is an exopeptidase, aminopeptidase N (APN, EC 3.4.11.2). Biological studies performed on rat brain and spinal cord slices (3, 4) have shown that thiorphan, a selective NEP inhibitor, or bestatin, an APN inhibitor, did not significantly prevent [ 3 H]Met-enkephalin catabolism whereas their combination resulted in a clear reduction of the peptide degradation. This result has been confirmed in vivo. Thus, because of the complementary role of NEP and APN in e...

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Section: Discussionmentioning

confidence: 99%

Aminophosphinic inhibitors as transition state analogues of enkephalin-degrading enzymes: A class of central analgesics

Chen

Noble

Coric

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

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“…These features explain the large range of biological activities displayed by the members of this important class of compounds and the applications. [2][3][4][5] They have been found in areas ranging from medicine to agriculture, for example, as antibiotics, 6 enzyme inhibitors, 7 anticancer agents 8 and herbicides. 9,10 These biological properties mostly are associated with the tetrahedral structure of the phosphonyl group acting as a "transition-state" analogue.…”

Section: Introductionmentioning

confidence: 99%

Methods for the synthesis of α-heterocyclic/heteroaryl-α-aminophosphonic acids and their esters

Ali¹,

Abdel‐Kariem²

2015

Arkivoc

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“…A great deal of attention is bestowed on them 1,2 as they are structural analogues of the corresponding α-amino acids. Further, heterocyclic phosphonates and ω-aminophosphonates are an important class of compounds, with several potential applications in medicine as anticancer agents, 3 potent enzyme inhibitors, 4 antiviral agents, 5 peptide mimetics, 6 haptens of catalytic antibodies, antibiotics, and pharmacological agents. 7 Their diverse applications include inhibition of synthase, 8 HIV protease, 9 renin, 10 and PTPases.…”

Section: Introductionmentioning

confidence: 99%

Microwave Assisted One-pot Synthesis of Novel α-Aminophosphonates and heir Biological Activity

Rao¹,

Rao²,

Rao³

et al. 2010

Bulletin of the Korean Chemical Society

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A simple and efficient synthesis of various α-aminophosphonates (3a-l) by the reaction of substituted aromatic/heterocyclic aldehydes, 2-amino-6-methoxy-benzothiazole and dibutyl/diphenyl phosphites under microwave irradiation without catalyst was accomplished. The phosphonates were characterized by elemental analysis, IR, 1 H, 13 C-and 31 P-NMR spectra. They showed promising antimicrobial, anti-oxidant activities depending on the nature of bioactive groups at the α-carbon.

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Non-peptidic inhibitors of neutral endopeptidase 24.11 1. Discovery and optimization of potency

Cited by 65 publications

References 15 publications

Aminophosphinic inhibitors as transition state analogues of enkephalin-degrading enzymes: A class of central analgesics

Aminophosphinic inhibitors as transition state analogues of enkephalin-degrading enzymes: A class of central analgesics

Methods for the synthesis of α-heterocyclic/heteroaryl-α-aminophosphonic acids and their esters

Microwave Assisted One-pot Synthesis of Novel α-Aminophosphonates and heir Biological Activity

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