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. 2007 Mar 1;15(5):2054-80.
doi: 10.1016/j.bmc.2006.12.031. Epub 2006 Dec 23.

Azetidinones as vasopressin V1a antagonists

Christophe D Guillon  1 , Gary A Koppel, Michael J Brownstein, Michael O Chaney, Craig F Ferris, Shi-Fang Lu, Karine M Fabio, Marvin J Miller, Ned D Heindel, David C Hunden, Robin D G Cooper, Stephen W Kaldor, Jeffrey J Skelton, Bruce A Dressman, Michael P Clay, Mitchell I Steinberg, Robert F Bruns, Neal G Simon
Affiliations

Azetidinones as vasopressin V1a antagonists

Christophe D Guillon et al. Bioorg Med Chem. .

Abstract

The azetidinone LY307174 (1) was identified as a screening lead for the vasopressin V1a receptor (IC50 45 nM at the human V1a receptor) based on molecular similarity to ketoconazole (2), a known antagonist of the luteinizing hormone releasing hormone receptor. Structure-activity relationships for the series were explored to optimize receptor affinity and pharmacokinetic properties, resulting in compounds with Ki values <1nM and brain levels after oral dosing approximately 100-fold higher than receptor affinities.

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Figures

Figure 1
Figure 1
Receptor crosstalk as a screening tool
Figure 2
Figure 2
Figure 3
Figure 3
X-ray structure/absolute configuration of 7
Figure 4
Figure 4
SAR overview of Zone A, 20 compounds prepared
Figure 5
Figure 5
SAR overview of Zone B, 3 compounds prepared
Figure 6
Figure 6
SAR overview of Zone C, 35 compounds prepared
Figure 7
Figure 7
Acceptability of benzylamide in Zone D
Figure 8
Figure 8
SAR overview of Zone D
Figure 9
Figure 9
Non-additivity of the Zone C pivaloyl and Zone D piperidyl-ethyl-piperidine substitutions.
Figure 10
Figure 10
Rationale for aminomalonate platform
Figure 11
Figure 11
D,L-aminomalonyl platform and attendant V1a affinity
Figure 12
Figure 12
L-aspartyl platform and attendant V1a affinity
Figure 13
Figure 13
D-aspartyl platform and attendant V1a affinity
Figure 14
Figure 14
L-glutamyl platform and attendant V1a affinity
Figure 15
Figure 15
D-glutamyl platform and attendant V1a affinity
Figure 16
Figure 16
Structures and human V1a binding affinities of 50, 51 and 53
Figure 17
Figure 17
Oral pharmacokinetics of SRX246 and SRX251 in rats.
Figure 18
Figure 18
Aminomalonic acid derivatives.
Figure 19
Figure 19
L-aspartic acid derivatives.
Figure 20
Figure 20
D-aspartic acid derivatives.
Figure 21
Figure 21
Additional D-aspartic acid derivatives
Figure 22
Figure 22
L-glutamic acid derivatives.
Figure 23
Figure 23
Additional L-glutamic acid derivatives.
Figure 24
Figure 24
D-glutamic acid derivatives
Scheme 1
Scheme 1
Scheme 2
Scheme 2
Synthesis of 33 and analogs
Scheme 3
Scheme 3
Syntheses of L-aspartic and L-glutamic acid derivatives. R = −OSu, i: HNR1R2/THF; R = −OH, ii: HNR1R2/HOBT/EDC,HCl/CH2Cl2.
Scheme 4
Scheme 4
Syntheses of D-aspartic and D-glutamic acid derivatives
Scheme 5
Scheme 5
Synthesis of additional L-glutamic acid derivatives
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References

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