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Emending Development of the first drug.
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Emending SAR
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=== Structure-activity relationship (SAR) and pharmacophore ===
=== Structure-activity relationship (SAR) and pharmacophore ===
There are at least three essential elements which are important for the interaction of a ligand to the NK1 receptor. Firstly the ion-pair site interaction with the bridgehead nitrogen, secondly the accessory binding site interaction with the benzhydryl group and thirdly the specific site interaction with the (2-methoxybenzyl) amino side chain.
There are at least three essential elements which are important for the interaction of a ligand to the NK<sub>1</sub> receptor. Firstly the ion-pair site interaction with the bridgehead nitrogen, secondly the accessory binding site interaction with the benzhydryl group and thirdly the specific site interaction with the (2-methoxybenzyl) amino side chain.
Studies have shown that compounds with piperidine ring have selectivity for NK<sub>1</sub> over NK<sub>2</sub>, NK<sub>3</sub>, opioid and 5-HT receptors. By adding an N-heteroaryl-2-phenyl-3-(benzyloxy) group to the piperidine, a NK<sub>1</sub> selective antagonist is produced. Studies have also shown that the dihedral angle between groups on C-2 and C-3 in CP-99994 is critical for activity of the NK1 antagonists.<ref name="Datar_2004"/> The bridgehead basic nitrogen is thought to interact with the NK1 receptor by mediating its recognition through ion pair site.<ref name="Seto_2005"/> It has been found that the basic nitrogen atoms in pyrido[3,4-b]pyridine do have an anchoring function in the phospholipid component of the cell membrane.<ref name="Datar_2004"/>
Studies have shown that compounds with piperidine ring have selectivity for NK<sub>1</sub> over NK<sub>2</sub>, NK<sub>3</sub>, opioid and 5-HT receptors. By adding an N-heteroaryl-2-phenyl-3-(benzyloxy) group to the piperidine, a NK<sub>1</sub> selective antagonist is produced. Studies have also shown that the dihedral angle between groups on C-2 and C-3 in CP-99994 is critical for activity of the NK<sub>1</sub> antagonists.<ref name="Datar_2004"/> The bridgehead basic nitrogen is thought to interact with the NK<sub>1</sub> receptor by mediating its recognition through ion pair site.<ref name="Seto_2005"/> It has been found that the basic nitrogen atoms in pyrido[3,4-b]pyridine do have an anchoring function in the phospholipid component of the cell membrane.<ref name="Datar_2004"/>


In the development of MK-869 it was discovered that 3,5-disubstitution of the benzyl ring in the ether series gave greater potency than the 2-methoxy substitution in earlier benzylamine structures. It also was revealed that the 3,5-bis-trifluoromethylphenyl group appeared to be especially important and it is believed that it enhances activity in vivo and improves metabolism. Other groups, like the ortho-methoxyphenyl group can be important in specific cases, but are thought to play a greater role in ligand preorganization through intramolecular hydrogen bonding, rather than through direct interaction with binding site residue.<ref name="Humphrey__2003"/>
In the development of MK-869 it was discovered that 3,5-disubstitution of the benzyl ring in the ether series gave greater potency than the 2-methoxy substitution in earlier benzylamine structures. It also was revealed that the TFMP group appeared to be especially important and it is believed that it enhances activity in vivo and improves metabolism. Other groups, like the ortho-methoxyphenyl group can be important in specific cases, but are thought to play a greater role in ligand preorganization through intramolecular hydrogen bonding, rather than through direct interaction with binding site residue.<ref name="Humphrey__2003"/>
The presence of an intramolecular face-to-face π π interaction between two aromatic rings is a common feature of high affinity NK<sub>1</sub> antagonists. This feature is thought to be important in stabilizing the bioactive conformation. This interaction can be increased with a conformationally restricted system, such as an eight- membered ring introduced into the naphthyridine ring.<ref name="Seto_2005"/>
The presence of an intramolecular face-to-face π π interaction between two aromatic rings is a common feature of high affinity NK<sub>1</sub> antagonists. This feature is thought to be important in stabilizing the bioactive conformation. This interaction can be increased with a conformationally restricted system, such as an eight- membered ring introduced into the naphthyridine ring.<ref name="Seto_2005"/>


Revision as of 13:28, 11 November 2008

History

In 1931, von Euler and Gaddum discovered Substance P (SP) in horse brain and intestine. The substance showed strong vasodilatory effects and contractile activity on the rabbit gut. A great effort was put in to purifying this substance from diverse mammalian tissue, but without success for over 30 years. Couple of nonmammalian peptides that elicited the same vasodilatory and contractile effects as SP were discovered by Erspamer in the early ’60. These peptides had a common C-terminal sequence (Phe-Xaa-Gly-Leu-MetNH2) and were grouped together as tachykinins. In 1971 Chang managed to purify SP from horse intestine and identify its amino-acid sequence and as a result SP was classified as a mammalian tachykinin. In the 70´s it became clear that SP was a neuropeptide that was common in the central and peripheral nervous system. In the mid 80’s, the additional mammalian tachykinin neurokinin A (NKA) and neurokinin B (NKB) were discovered.[1][2] This led to further research, resulting with the isolation of the genes that encoded the mammalian tachykinins and eventually the discovery of three different tachykinin receptors. In 1984 it was decided that the tachykinin receptors should be called tachykinin NK1 receptor, tachykinin NK2 receptor and tachykinin NK3 receptor.[1][3] Many biological researches on the function of tachykinins revealed its numerous functions and interest in neurokinin receptor antagonists development arose.[2] In the 80’s, several peptide antagonists derived from SP were the first NK1 receptor antagonists. However, these compounds had the same problems most peptide compounds have, related to selectivity, potency, solubility and bioavailability. For that reason pharmaceutical companies concentrated on developing non-peptid NK1 receptor antagonists and in 1991 three different companies revealed their first results. Since then non-peptid NK1 receptor antagonists have been extensively researched and many structures and patents have appeared, and in 2003 the first NK1 receptor antagonist, aprepitant (Emend®), received marketing approval from the FDA.[4][5][6]


The neurokinin-1 receptor

Tachykinins are a family of neuropeptides that share the same hydrophobic C-terminal region with the amino-acid sequence Phe-X-Gly-Leu-Met-NH2, where X represents a hydrophobic residue that is either an aromatic or a beta-branched aliphatic. The N-terminal region varies between different tachykinins.[7][8][9] The term tachykinin originates in the rapid onset of action the peptides cause in smooth muscles.[9] SP is the most researched and potent member of the tachykinin family. It is an undecapeptide with the amino-acid sequence Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2.[7] SP binds to all three of the tachykinin receptors, but it binds most strongly to the NK1 receptor.[8] Tachykinin NK1 receptor, often referred to as NK1 receptor, is a member of family 1 (rhodopsin-like) of G protein-coupled receptors.[2] NK1 receptor consists of 407 amino-acid residues and it has a molecular weight of 58.000.[7][10] NK1 receptor, as well as the other tachykinin receptors, is made of seven hydrophobic transmembrane (TM) domains with three extracellular and three intracellular loops, an extracellular amino-terminus and a cytoplasmic carboxy-terminus. The loops have couple of functional sites, including two cysteines for a disulfide bridge, Asp-Arg-Tyr that is responsible for association with arrestin and Lys/Arg-Lys/Arg-X-X-Lys/Arg that interacts with G-proteins.[2][10]

Distribution and function of the receptor

The NK1 receptor can be found in both the central and peripheral nervous system. It is present in neurons, vascular endothelial cells, muscle, gastrointestinal tracts, genitourinary tract, pulmonary tissue, thyroid gland and different types of immune cells.[2][9][10] The binding of SP to the NK1 receptor has been associated with the transmission of stress signals and pain, contraction of smooth muscles and inflammation.[11] NK1 antagonists have also been studied in migraine, emesis and psychiatric disorder. In fact, aprepitant has been proved effective in a number of pathophysiological models of anxiety and depression.[6] Other disease that the NK1 receptor system is implicated in include asthma, rheumatoid arthritis and gastrointestinal disorder.[5]


Drug discovery and development

Fig 1. CP-96345
Fig 2. CP-99994

In 1991, three different research groups were researching different NK1 receptor antagonists by screening of chemical collections. Easman Kodak discovered steroid series of tachykinin NK1 receptor antagonists that gave couple of compounds but didn’t have sufficient affinity for the NK1 receptor, despite structure-activity relationship (SAR) studies that were performed. This class proved to have significant toxicity. Even though many derivates of the steroid compounds have been synthesized, biological activity hasn’t been improved.[6][12]

Fig 3. Development of MK-869 / aprepitant

Rhone-Poulnec discovered the compound RP 67580 which has high affinity for the NK1 receptor in rats and mice but not in humans. SAR studies that were performed in order to improve the selectivity for the human NK1 receptor resulted in the development of a compound called RPR 100893. This compound showed good activity in vivo and in models of pain and was developed up to phase II for the treatment of migraine but then terminated, as has happened to other NK1 antagonists that have been tested for the same indication.[6][12]

The third company, Pfizer, discovered a benzylamino quinuclidine structure, which was called CP 96345. CP 96345 has a rather simple structure, composed of a rigid quinuclidine scaffold containing a basic nitrogen atom, a benzhydril moiety and an o-methoxy-benzylamine group. This compound showed high affinity for the NK1 receptor, but it also interacted with Ca2+ binding sites. Strongly basic quinuclidine nitrogen on the compound was considered to be responsible for this Ca2+ binding, which caused a number of systemic effects, unrelated to the blocking of the NK1 receptor. For that reason and also to simplify the structure, alkylation at this site was performed to produce analogs. The compound CP 99994 was synthesized by replacing the quinuclidine ring with a piperidine ring and benzhydryl moiety by a benzyl group.[6][12] CP 99994 had a high affinity for the human NK1 receptor and it started a great amount of structure-activity studies, with the purpose to identify the structural requirements for high affinity interaction with the NK1 receptor, as well as making the molecule even simpler and improve its chemico-physical and pharmacological properties.[12] CP 99994 eased dental pain in humans and made it to Phase II clinical trials, but was discontinued because of poor bioavailability. (ATH…). Pfizer researched several other related NK1 receptor antagonists, and one of them, CP 122721 also made it to Phase II clinical trials for treatment of depression, emesis and inflammatory diseases before it was discontinued.[6]

Development of the first drug

In 1993 Merck started performing SAR studies of NK1 receptor antagonists, based on both CP 96345 and CP 99994. The compounds that were selected for development were based on CP 99994. L-733,060 is one of those compounds, and it has a 3,5-bistrifluoromethyl benzylether piperidine in the place of 2-methoxy benzylamine moiety of CP 99994 compound. To improve oral bioavailability the piperidine nitrogen was functionalized in order to reduce its basic nature. The group that gave the best effects on bacicity was 3-oxo-1,2,4-triazol-5-yl moiety and it gave compounds such as L-741,671 and L-742,694. A morpholine nucleus that was introduced in L-742,694 was found to enhance NK1 binding affinity.[5] This nucleus was preserved in further modifications. In order to prevent possible metabolic deactivation several refinements such as methylation on the C alfa of the benzyl ring and fluorination on the phenyl ring were introduced. These changes produced the compound MK-869, which showed high affinity for the NK1 receptor and high oral activity. MK-869 is also called aprepitant and was studied in pain, migraine, emesis and psychiatric disorder. Those studies led to the FDA approved drug Emend®, which is indicated for emesis.[6]

Binding pocket

There is more than one ligand binding domain on the NK1 receptor for the non-peptide antagonists and they can be found in various places. The main ligand binding site is in the hydrophobic core between the loops and the outer segments of TM3 – TM7.[10] Several residues, such as Gln165 (TM4), His197 (TM5), His265 (TM6) and Tyr287 (TM7) are involved in the binding of many non-peptide antagonists of the NK1 receptors.[1][10] It has been stated that Ala-replacement of His197 decreases the binding affinity of CP-96345 for the NK1 receptor. His197 interacts with the benzhydryl moiety of CP-96345. Experiments have showed that replacing Val116 (TM3) and Ile290 (TM7) decreases the binding affinity of CP-96345. Evidence provide that these residues probably do not interact with antagonists, but would rather indirectly influence the overall conformation of the antagonist binding site. The residue Gln165 (TM4) has also showed to be meaningful for the binding of several nonpeptide antagonists, possibly through the formation of a hydrogen bond.[12][13] Phe268 and Tyr287 have been proposed as possible contact points for both agonist and antagonist binding domain.[10]

The significant of His265 has been confirmed in the binding of antagonists to NK1 receptor. His265 interacts favorable with the 3,5-bis-trifluoromethylphenyl group (TFMP group) of an analog CP-96345. Despite this it has been demonstrated that Ala-replacement of His265 did not affect the binding affinity of CP-96345. [5]

Some other residues which are thougt to be involved in the binding of non-peptide antagonists to NK1 receptor are Ser169, Glu193, Lys194, Phe264, Phe267, Pro271 and Tyr272. Each structural class of non-peptide NK1 receptor antagonists appear to interact with a specific set of residues within the common binding pocket.[1][10]

Structure-activity relationship (SAR) and pharmacophore

There are at least three essential elements which are important for the interaction of a ligand to the NK1 receptor. Firstly the ion-pair site interaction with the bridgehead nitrogen, secondly the accessory binding site interaction with the benzhydryl group and thirdly the specific site interaction with the (2-methoxybenzyl) amino side chain. Studies have shown that compounds with piperidine ring have selectivity for NK1 over NK2, NK3, opioid and 5-HT receptors. By adding an N-heteroaryl-2-phenyl-3-(benzyloxy) group to the piperidine, a NK1 selective antagonist is produced. Studies have also shown that the dihedral angle between groups on C-2 and C-3 in CP-99994 is critical for activity of the NK1 antagonists.[9] The bridgehead basic nitrogen is thought to interact with the NK1 receptor by mediating its recognition through ion pair site.[11] It has been found that the basic nitrogen atoms in pyrido[3,4-b]pyridine do have an anchoring function in the phospholipid component of the cell membrane.[9]

In the development of MK-869 it was discovered that 3,5-disubstitution of the benzyl ring in the ether series gave greater potency than the 2-methoxy substitution in earlier benzylamine structures. It also was revealed that the TFMP group appeared to be especially important and it is believed that it enhances activity in vivo and improves metabolism. Other groups, like the ortho-methoxyphenyl group can be important in specific cases, but are thought to play a greater role in ligand preorganization through intramolecular hydrogen bonding, rather than through direct interaction with binding site residue.[5] The presence of an intramolecular face-to-face π π interaction between two aromatic rings is a common feature of high affinity NK1 antagonists. This feature is thought to be important in stabilizing the bioactive conformation. This interaction can be increased with a conformationally restricted system, such as an eight- membered ring introduced into the naphthyridine ring.[11]


See also

Substance P

G protein-copuled receptors

Tachykinin

Aprepitant


References

  1. ^ a b c d Maggi, C. A. (September 1994), "Mammalian Tachykinin Receptors", General Pharmacology, 26 (5): 911–944{{citation}}: CS1 maint: date and year (link)
  2. ^ a b c d e Satake, H.; Kawada, T. (August 2006), "Overview of the primary structure, tissue-distribution, and functions of tachykinins and their receptors", Current Drug Targets, 7 (8): 963–974{{citation}}: CS1 maint: date and year (link)
  3. ^ Saria, A. (June 1999), "The Tachykinin NK1 receptor in the brain: pharmacology and putative functions", European Journal of Pharmacology, 375 (1–3): 51–60{{citation}}: CS1 maint: date and year (link)
  4. ^ Hoffman, T.; Bös, M.; Stadler, H.; Schnider, P.; Hunkeler, W.; Godel, T.; Galley, G.; Ballard, T. M.; Higgins, G. A.; Poli, S. M.; Sleight, A. J. (March 2006), "Design and synthesis of a novel, achiral class of highly potent and selective, orally active neurokinin-1 receptor antagonists", Bioorganic & Medicinal Chemistry Letters, 16 (5): 1362=1365{{citation}}: CS1 maint: date and year (link)
  5. ^ a b c d e Humphrey, J. M. (2003), "Medicinal Chemistry of Selective Neurokinin-1 Antagonists", Current Topics in Medicinal Chemistry, 3 (12): 1423–1435{{citation}}: CS1 maint: date and year (link)
  6. ^ a b c d e f g Quartara, L.; Altamura, M. (August 2006), "Tachykinin receptors antagonists: From research to clinic", Current drug targets, 7 (8): 975–992{{citation}}: CS1 maint: date and year (link)
  7. ^ a b c Ho, W. Z.; Douglas, S. D. (December 2004), "Substance P and neurokinin-1 receptor modulation of HIV", Journal of Neuroimmunology, 157 (1–2): 48–55{{citation}}: CS1 maint: date and year (link)
  8. ^ a b Page, N. M. (August 2005), "New challenges in the study of the mammalian Tachykinins", Peptides, 26 (8): 1356–1368{{citation}}: CS1 maint: date and year (link)
  9. ^ a b c d e Datar, P.; Srivastava, S.; Coutinho, E.; Govil, G. (2004), "Substance P: Structure, Function, and Therapeutics", Current Topics in Medicinal Chemistry, 4 (1): 75–103{{citation}}: CS1 maint: date and year (link)
  10. ^ a b c d e f g Almeida, T. A.; Rojo, J.; Nieto, P. M.; Hernandez first4 = M.; Martin, J. D.; Candenas, M. L. (August 2004), "Tachykinins and Tachykinins Receptors: Structure and Activity Relationships", Current Medicinal Chemistry, 11 (15): 2045–2081 {{citation}}: Missing pipe in: |last4= (help)CS1 maint: date and year (link) CS1 maint: numeric names: authors list (link)
  11. ^ a b c Seto, S.; Tanioka, A.; Ikeda, M.; Izawa, S. (March 2005), "Design and synthesis of novel 9-substituted-7-aryl-3,4,5,6-tetrahydro-2H-pyrido[4,3-b]- and [2,3-b]-1,5-oxazocin-6-ones as NK1 antagonists", Bioorganic and Medicinal Chemistry Letters, 15 (5): 1479–1484{{citation}}: CS1 maint: date and year (link)
  12. ^ a b c d e Quartara, L.; Maggi, C. A. (December 1997), "The tachykinin NK1 receptor. Part I: Ligands and mechanisms of cellular activation", Neuropeptides, 31 (6): 537–563{{citation}}: CS1 maint: date and year (link)
  13. ^ Pennefather, J. N.; Lecci, A.; Candenas, M. L.; Patak, E.; Pinto, F. M.; Maggi, C. A. (2004), "Tachykinins and tachykinin receptors: a growing family", Life Sciences, 74 (12): 1445–1463
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