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.2009 Apr;4(4):505-11.
doi: 10.1002/cmdc.200800357.

Synthesis, SAR and unanticipated pharmacological profiles of analogues of the mGluR5 ago-potentiator ADX-47273

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Synthesis, SAR and unanticipated pharmacological profiles of analogues of the mGluR5 ago-potentiator ADX-47273

Darren W Engers et al. ChemMedChem.2009 Apr.

Abstract

An iterative analogue library synthesis strategy rapidly developed comprehensive SAR for the mGluR5 ago-potentiator ADX-47273. This effort identified key substituents in the 3-position of oxadiazole that engendered either mGluR5 ago-potentiation or pure mGluR5 positive allosteric modulation. The mGluR5 positive allosteric modulators identified possessed the largest fold shifts (up to 27.9-fold) of the glutamate CRC reported to date as well as providing improved physiochemical properties.

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Figures

Figure 1
Figure 1
Representative Chemotypes of mGluR5 Positive Allosteric Modulators1,2 and3 and the mGluR5 Ago-potentiator4.
Figure 2
Figure 2
In vitro profile of the mGluR5 ago-potentiator ADX-47273 (5), highlighting the intrinsic allosteric agonist activity (5 alone) to activate mGluR5 in the absence of an EC20 of glutamate. In the presence of an EC20 of glutamate, ADX-47273 (5) is a potent mGluR5 positive allosteric modulator with an EC50 for potentiation of 168 nM and a 9-fold shift of the glutamate response curve at 1 μM.
Figure 3
Figure 3
Three key areas to explore in the lead optimization of ADX-47273 (5).
Figure 4
Figure 4
Second generation (3 × 12) library design for analogues10–12.
Figure 5
Figure 5
In vitro pharmacological profile of10c. A) Raw calcium fluorescence trace showing mGluR5 receptor activation (agonism) in the presence of10c alone added at t=4s, followed by potentiation of an EC20 concentration of glutamate added 140s later, indicating10c is also an mGluR5 PAM; B) Concentration-response-curves for both potentiation (EC50 = 133 nM) and agonism (EC50 = 5 μM); C) Fold-shift assay employing 370 nM concentration of10c elicits a 5-fold leftward shift of the glutamate CRC.
Figure 6
Figure 6
In vitro pharmacological profile of12b. A) Raw calcium fluorescence trace showing no mGluR5 receptor activation (agonism) in the presence of12b alone added at t=4s, followed solely by potentiation of an EC20 concentration of glutamate added 140s later, indicating12b is an mGluR5 PAM; B) Concentration-response-curve for potentiation (EC50 = 244 nM) and again showing no mGluR5 activation by12b/vehicle alone; C) Fold-shift assay employing 1μM concentration of12b elicits a 14-fold leftward shift of the glutamate CRC.
Figure 7
Figure 7
Identification of an mGluR5 NAM within the ADX PAM Chemotype.
Scheme 1
Scheme 1
Synthesis of analogs10–12 of ADX-47273 (5). Reagents and conditions: Route (I): a) (S)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid, EDCI, HOBt, 1,4-dioxane, reflux (R = 4-FPh, 51%; R = 2-thienyl, 66%; R = 2-pyridyl, 44%); b) 4 N HCl/dioxane, DCM (82–99%); c) R1COCl, DIEA, DCM (74–95%); Route (II): d) SOCl2, MeOH (99%); e) (i) R1COCl, DIEA, DCM; (ii) LiOH, THF/MeOH (88–92%); f) (Z)-N′-hydroxyimidamide, EDCI, HOBt, 1,4-dioxane, reflux (R = 4-FPh, 56%; R = 2-thienyl, 68%; R = 2-pyridyl, 57%).
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References

    1. Andreasen NC. Brain Res Rev. 2000;31:106–112. - PubMed
    2. Karayiorgou M. Clin Neurosci Res. 2001;1:158–163.
    3. Meador-Woodruff JH, Healy DJ. Brain Res Rev. 2000;31:288–294. - PubMed
    1. Marino PJ, Conn PJ. Curr Drug Targets – CNS & Neur Disord. 2002;1:1–16. - PubMed
    2. Carlsson A, Lindqvist M. Acta Pharmacol Toxicol. 1963;20:140–144. - PubMed
    3. Seeman P, Lee T, Chau-Wong M, Wong K. Nature. 1976;261:717–719. - PubMed
    4. Seeman P, Lee T. Science. 1975;188:1217–1219. - PubMed
    1. Bertolino A, Breier A, Callicott JH, Adler C, Mattay VS, Shapiro M, Frank JA, Pickar D, Weinberger DR. Neuropsychopharmacology. 1999;22:125–132. - PubMed
    2. Laruelle M, Abi-Dargham A, van Dyck CH, Gil R, D’Souza CD, Erdos J, McCance E, Rosenblatt W, Fingado C, Zoghbi SS, Baldwin RM, Seibyl JP, Krystal JH, Charney DS, Innis RB. Proc Nat Acad of Sci USA. 1996;93:9235–9240. - PMC - PubMed
    3. Laruelle M, D’Souza CD, Baldwin RM, Abi-Dargham A, Kanes SJ, Fingado CL, Seibyl JP, Zoghbi SS, Bowers MB, Jatlow P, Charney DS, Innis RB. Neuropsychopharmacology. 1997;17:162–174. - PubMed
    4. Angrist BM. In: Amphetamine and its analogues. Cho, Segals, editors. Academic Press; San Diego, CA: 1994. pp. 387–414.
    1. Ducan GE, Lieberman JA. Mol Psychiatry. 1999;4:418–428. - PubMed
    1. Farde L, Nordstrom AL, Wiesel FA, Pauli S, Halldin C, Sedvall G. Arch Gen Psychiatry. 1992;49:538–544. - PubMed

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