Synthesis and structure-activity relationships for a series of substituted pyrrolidine NK1/NK2 receptor antagonists

Burkholder, Timothy P.; Kudlacz, Elizabeth M.; Maynard, George D.; Liu, Xiao-Gao; Le, Tieu-Binh; Webster, Mark E.; Horgan, S. W.; Wenstrup, David L.; Freund, David W.; Boyer, Fred E.; Bratton, Larry; Gross, Raymond S.; Knippenberg, Robert W.; Logan, Deborah E.; Jones, Bryan K.; Chen, Teng‐Man; Geary, J L; Correll, Melinda A.; Poole, James; Mandagere, Arun K.; Thompson, Thomas N.; Hwang, Kwang Woo

doi:10.1016/s0960-894x(97)10013-0

Cited by 22 publications

(11 citation statements)

References 18 publications

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“…Substitution at 2-naphthalene position increases NK 1 potency while alterations in piperidine region increases the NK 2 potency. Thus factors affecting the balance of NK 1 and NK 2 selectivity are identified and several dual acting antagonists have now been developed [135,[260][261][262][263][264][265][266]. Boks et.…”

Section: Non-peptide Antagonistsmentioning

confidence: 99%

Substance P: Structure, Function, and Therapeutics

Datar

Srivastava²,

Coutinho³

et al. 2004

CTMC

148

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Extensive efforts since 1931, on the structural determination of the mammalian tachykinin SP by NMR, CD and IR have turned out to be inconclusive. Studies are now being concentrated on the structural properties and characteristics of various NK receptors (NK(1), NK(2) and NK(3)) with the help of genetics, cloning, receptor engineering, mutagenesis and modeling. This knowledge is now being fruitfully used in the development of non-peptide NK(1) receptor antagonists that essentially block the pharmacological effects of SP. It is now being realized that the simultaneous blockade of two or more receptors gives promising results in emesis, depression and pulmonary obstructive diseases. In addition to the synthetic compounds, the discovery of antagonists from natural origin has added a great value to this field. In this review we have made an attempt to present the structural characteristics of SP, its analogs and antagonists, the structural characteristics of the NK receptor, and structure activity relationships that have helped to improve the therapeutic utilities of SP antagonists.

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Section: Non-peptide Antagonistsmentioning

confidence: 99%

Substance P: Structure, Function, and Therapeutics

Datar

Srivastava²,

Coutinho³

et al. 2004

CTMC

148

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“…To explore these possibilities, we sought to introduce NK 1 activity while maintaining NK 2 activity in structures related to 1. Approaches to the development of dual NK 1 /NK 2 antagonists have been demonstrated by starting from other NK 2 selective agents [11][12][13][14][15] and by starting from NK 1 selective agents. 5 Our subsequent efforts 16,17 led to the discovery of the NK 1 /NK 2 dual antagonist ZD6021 (2).…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and SAR of Tachykinin Antagonists: Modulation of Balance in NK₁/NK₂ Receptor Antagonist Activity

et al. 2002

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Through optimization of compounds based on the dual NK(1)/NK(2) antagonist ZD6021, it was found that alteration of two key regions could modulate the balance of NK(1) and NK(2) potency. Substitution of the 2-naphthalene position in analogues of ZD6021 resulted in increased NK(1) potency and thus afforded NK(1) preferential antagonists. Alterations of the piperidine region could then increase NK(2) potency to restore dual NK(1)/NK(2) selectivity. Through these efforts, three novel receptor antagonists from a single chemically related series were identified; two are dual NK(1)/NK(2) antagonists, and the third is an NK(1) preferential antagonist. In this paper, the factors affecting the balance of NK(1) and NK(2) selectivity in this series are discussed and the in vitro and in vivo properties of the novel antagonists are described.

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“…Angle is the deviation from ideal hydrogen bond geometry (ϕ as defined in Figure 3). determined by the substitution pattern of the pharmacophore elements A, B and C. An unsubstituted phenyl ring and a 3,4-di-chlorophenyl as pharmacophore elements A and B, respectively, is optimal for NK2 activity [33,34]. 3,5-Di-methylphenyl, 3,5-ditrifluoromethylphenyl and 3,4,5-tri-methoxyphenyl as pharmacophore element A is optimal for NK1 activity whereas substituents in pharmacophore element B are of minor importance for NK1 activity [33,35,36].…”

Section: Selectivity For the Nk1 Nk2 And Nk3 Receptorsmentioning

confidence: 99%

Pharmacophore and receptor models for neurokinin receptors

Poulsen

Bjørnholm²,

Gundertofte³

et al. 2003

J Comput Aided Mol Des

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Three neurokinin (NK) antagonist pharmacophore models (Models 1-3) accounting for hydrogen bonding groups in the 'head' and 'tail' of NK receptor ligands have been developed by use of a new procedure for treatment of hydrogen bonds during superimposition. Instead of modelling the hydrogen bond acceptor vector in the strict direction of the lone pair, an angle is allowed between the hydrogen bond acceptor direction and the ideal lone pair direction. This approach adds flexibility to hydrogen bond directions and produces more realistic RMS values. By using this approach, two novel pharmacophore models were derived (Models 2 and 3) and a hydrogen bond acceptor was added to a previously published NK2 pharmacophore model [Poulsen et al., J. Comput.-Aided Mol. Design, 16 (2002) 273] (Model 1). Model 2 as well as Model 3 are described by seven pharmacophore elements: three hydrophobic groups, three hydrogen bond acceptors and a hydrogen bond donor. Model 1 contains the same hydrophobic groups and hydrogen bond donor as Models 2 and 3, but only one hydrogen bond acceptor. The hydrogen bond acceptors and donor are represented as vectors. Two of the hydrophobic groups are always aromatic rings whereas the other hydrophobic group can be either aromatic or aliphatic. In Model 1 the antagonists bind in an extended conformation with two aromatic rings in a parallel displaced and tilted conformation. Model 2 has the same two aromatic rings in a parallel displaced conformation whereas Model 3 has the rings in an edge to face conformation. The pharmacophore models were evaluated using both a structure (NK receptor homology models) and a ligand based approach. By use of exhaustive conformational analysis (MMFFs force field and the GB/SA hydration model) and least-squares molecular superimposition studies, 21 non-peptide antagonists from several structurally diverse classes were fitted to the pharmacophore models. More antagonists could be fitted to Model 2 with a low RMS and a low conformational energy penalty than to Models 1 and 3. Pharmacophore Model 2 was also able to explain the NK1, NK2 and NK3 subtype selectivity of the compounds fitted to the model. Three NK 7TM receptor models were constructed, one for each receptor subtype. The location of the antagonist binding site in the three NK receptor models is identical. Compounds fitted to pharmacophore Model 2 could be docked into the NK1, NK2 and NK3 receptor models after adjustment of the conformation of the flexible linker connecting the head and tail. Models I and 3 are not compatible with the receptor models.

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Synthesis and structure-activity relationships for a series of substituted pyrrolidine NK1/NK2 receptor antagonists

Cited by 22 publications

References 18 publications

Substance P: Structure, Function, and Therapeutics

Substance P: Structure, Function, and Therapeutics

Design, Synthesis, and SAR of Tachykinin Antagonists: Modulation of Balance in NK₁/NK₂ Receptor Antagonist Activity

Pharmacophore and receptor models for neurokinin receptors

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Synthesis and structure-activity relationships for a series of substituted pyrrolidine NK1/NK2 receptor antagonists

Cited by 22 publications

References 18 publications

Substance P: Structure, Function, and Therapeutics

Substance P: Structure, Function, and Therapeutics

Design, Synthesis, and SAR of Tachykinin Antagonists: Modulation of Balance in NK1/NK2 Receptor Antagonist Activity

Pharmacophore and receptor models for neurokinin receptors

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Product

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Design, Synthesis, and SAR of Tachykinin Antagonists: Modulation of Balance in NK₁/NK₂ Receptor Antagonist Activity