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Design, synthesis, and biological evaluation of (3R)-1,2,3,4-tetrahydro-7-hydroxy-N-[(1S)-1-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl]-3-isoquinolinecarboxamide (JDTic) analogues: in vitro pharmacology and ADME profile.
J Med Chem. 2014 Sep 11; 57(17):7367-81.JM

Abstract

JDTic analogues 4-15 which have the hydroxyl groups replaced with other groups were synthesized and their in vitro efficacy at the μ, δ, and κ opioid receptors determined and compared to JDTic using [(35)S]GTPγS assays. Compounds 4, 5, 6, 13, 14, and 15 had Ke = 0.024, 0.01, 0.039, 0.02, 0.11, and 0.041 nM compared to the Ke = 0.02 nM for JDTic at the κ receptor and were highly selective for the κ receptor relative to the μ and δ opioid receptors. Unexpectedly, replacement of the 3-hydroxyl substituent of the 4-(3-hydroxyphenyl) group of JDTic with a H, F, or Cl substituent leads to potent and selective KOR antagonists. In vitro studies to determine various ADME properties combined with calculated TPSA, clogP, and logBB values suggests that the potent and selective κ opioid receptors 4, 5, 13, and 14 deserve consideration for further development toward potential drugs for CNS disorders.

Authors+Show Affiliations

Research Triangle Institute , 3040 Cornwallis Road, P.O. Box 12194, Research Triangle Park, North Carolina 27709-6679, United States.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

25133923

Citation

Kormos, Chad M., et al. "Design, Synthesis, and Biological Evaluation of (3R)-1,2,3,4-tetrahydro-7-hydroxy-N-[(1S)-1-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl]-3-isoquinolinecarboxamide (JDTic) Analogues: in Vitro Pharmacology and ADME Profile." Journal of Medicinal Chemistry, vol. 57, no. 17, 2014, pp. 7367-81.
Kormos CM, Gichinga MG, Maitra R, et al. Design, synthesis, and biological evaluation of (3R)-1,2,3,4-tetrahydro-7-hydroxy-N-[(1S)-1-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl]-3-isoquinolinecarboxamide (JDTic) analogues: in vitro pharmacology and ADME profile. J Med Chem. 2014;57(17):7367-81.
Kormos, C. M., Gichinga, M. G., Maitra, R., Runyon, S. P., Thomas, J. B., Brieaddy, L. E., Mascarella, S. W., Navarro, H. A., & Carroll, F. I. (2014). Design, synthesis, and biological evaluation of (3R)-1,2,3,4-tetrahydro-7-hydroxy-N-[(1S)-1-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl]-3-isoquinolinecarboxamide (JDTic) analogues: in vitro pharmacology and ADME profile. Journal of Medicinal Chemistry, 57(17), 7367-81. https://doi.org/10.1021/jm5008177
Kormos CM, et al. Design, Synthesis, and Biological Evaluation of (3R)-1,2,3,4-tetrahydro-7-hydroxy-N-[(1S)-1-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl]-3-isoquinolinecarboxamide (JDTic) Analogues: in Vitro Pharmacology and ADME Profile. J Med Chem. 2014 Sep 11;57(17):7367-81. PubMed PMID: 25133923.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Design, synthesis, and biological evaluation of (3R)-1,2,3,4-tetrahydro-7-hydroxy-N-[(1S)-1-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl]-3-isoquinolinecarboxamide (JDTic) analogues: in vitro pharmacology and ADME profile. AU - Kormos,Chad M, AU - Gichinga,Moses G, AU - Maitra,Rangan, AU - Runyon,Scott P, AU - Thomas,James B, AU - Brieaddy,Lawrence E, AU - Mascarella,S Wayne, AU - Navarro,Hernán A, AU - Carroll,F Ivy, Y1 - 2014/08/25/ PY - 2014/8/19/entrez PY - 2014/8/19/pubmed PY - 2014/12/15/medline SP - 7367 EP - 81 JF - Journal of medicinal chemistry JO - J Med Chem VL - 57 IS - 17 N2 - JDTic analogues 4-15 which have the hydroxyl groups replaced with other groups were synthesized and their in vitro efficacy at the μ, δ, and κ opioid receptors determined and compared to JDTic using [(35)S]GTPγS assays. Compounds 4, 5, 6, 13, 14, and 15 had Ke = 0.024, 0.01, 0.039, 0.02, 0.11, and 0.041 nM compared to the Ke = 0.02 nM for JDTic at the κ receptor and were highly selective for the κ receptor relative to the μ and δ opioid receptors. Unexpectedly, replacement of the 3-hydroxyl substituent of the 4-(3-hydroxyphenyl) group of JDTic with a H, F, or Cl substituent leads to potent and selective KOR antagonists. In vitro studies to determine various ADME properties combined with calculated TPSA, clogP, and logBB values suggests that the potent and selective κ opioid receptors 4, 5, 13, and 14 deserve consideration for further development toward potential drugs for CNS disorders. SN - 1520-4804 UR - https://www.unboundmedicine.com/medline/citation/25133923/Design_synthesis_and_biological_evaluation_of__3R__1234_tetrahydro_7_hydroxy_N_[_1S__1_[[_3R4R__4__3_hydroxyphenyl__34_dimethyl_1_piperidinyl]methyl]_2_methylpropyl]_3_isoquinolinecarboxamide__JDTic__analogues:_in_vitro_pharmacology_and_ADME_profile_ L2 - https://doi.org/10.1021/jm5008177 DB - PRIME DP - Unbound Medicine ER -