Optimisation of in silico derived 2-aminobenzimidazole hits as unprecedented selective kappa opioid receptor agonists

Pradip K Sasmal; C Vamsee Krishna; S Sudheerkumar Adabala; khaji Abdul Rawoof; Amima Thadi; K Pawan Sukumar; Srisailam Cheera; Chandrasekhar Abbineni; K V L Narasimha Rao; A Prasanthi; Kamal Nijhawan; Mahaboobi Jaleel; Lakshmi Ramachandran Iyer; T Krishna Chaitanya; Nirbhay Kumar Tiwari; N Lavanya Krishna; Vijay Potluri; Ish Khanna; Thomas M Frimurer; Michael Lückmann; Øystein Rist; Lisbeth Elster; Thomas Högberg

doi:10.1016/j.bmcl.2014.12.064

Optimisation of in silico derived 2-aminobenzimidazole hits as unprecedented selective kappa opioid receptor agonists

Pradip K Sasmal, C Vamsee Krishna, S Sudheerkumar Adabala, khaji Abdul Rawoof, Amima Thadi, K Pawan Sukumar, Srisailam Cheera, Chandrasekhar Abbineni, K V L Narasimha Rao, A Prasanthi, Kamal Nijhawan, Mahaboobi Jaleel, Lakshmi Ramachandran Iyer, T Krishna Chaitanya, Nirbhay Kumar Tiwari, N Lavanya Krishna, Vijay Potluri, Ish Khanna, Thomas M Frimurer, Michael LückmannØystein Rist, Lisbeth Elster, Thomas Högberg

7 Citations (Scopus)

Abstract

Kappa opioid receptor (KOR) is an important mediator of pain signaling and it is targeted for the treatment of various pains. Pharmacophore based mining of databases led to the identification of 2-aminobenzimidazole derivative as KOR agonists with selectivity over the other opioid receptors DOR and MOR. A short SAR exploration with the objective of identifying more polar and hence less brain penetrant agonists is described herewith. Modeling studies of the recently published structures of KOR, DOR and MOR are used to explain the receptor selectivity. The synthesis, biological evaluation and SAR of novel benzimidazole derivatives as KOR agonists are described. The in vivo proof of principle for anti-nociceptive effect with a lead compound from this series is exemplified.

Original language	English
Journal	Bioorganic & Medicinal Chemistry Letters
Volume	25
Issue number	4
Pages (from-to)	887-92
Number of pages	6
ISSN	0960-894X
DOIs	https://doi.org/10.1016/j.bmcl.2014.12.064
Publication status	Published - 15 Feb 2015

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Sasmal, P. K., Krishna, C. V., Sudheerkumar Adabala, S., Rawoof, K. A., Thadi, A., Sukumar, K. P., Cheera, S., Abbineni, C., Rao, K. V. L. N., Prasanthi, A., Nijhawan, K., Jaleel, M., Ramachandran Iyer, L., Chaitanya, T. K., Tiwari, N. K., Krishna, N. L., Potluri, V., Khanna, I., Frimurer, T. M., ... Högberg, T. (2015). Optimisation of in silico derived 2-aminobenzimidazole hits as unprecedented selective kappa opioid receptor agonists. Bioorganic & Medicinal Chemistry Letters, 25(4), 887-92. https://doi.org/10.1016/j.bmcl.2014.12.064

Sasmal, PK, Krishna, CV, Sudheerkumar Adabala, S, Rawoof, KA, Thadi, A, Sukumar, KP, Cheera, S, Abbineni, C, Rao, KVLN, Prasanthi, A, Nijhawan, K, Jaleel, M, Ramachandran Iyer, L, Chaitanya, TK, Tiwari, NK, Krishna, NL, Potluri, V, Khanna, I, Frimurer, TM , Lückmann, M, Rist, Ø, Elster, L & Högberg, T 2015, 'Optimisation of in silico derived 2-aminobenzimidazole hits as unprecedented selective kappa opioid receptor agonists', Bioorganic & Medicinal Chemistry Letters, vol. 25, no. 4, pp. 887-92. https://doi.org/10.1016/j.bmcl.2014.12.064

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title = "Optimisation of in silico derived 2-aminobenzimidazole hits as unprecedented selective kappa opioid receptor agonists",

abstract = "Kappa opioid receptor (KOR) is an important mediator of pain signaling and it is targeted for the treatment of various pains. Pharmacophore based mining of databases led to the identification of 2-aminobenzimidazole derivative as KOR agonists with selectivity over the other opioid receptors DOR and MOR. A short SAR exploration with the objective of identifying more polar and hence less brain penetrant agonists is described herewith. Modeling studies of the recently published structures of KOR, DOR and MOR are used to explain the receptor selectivity. The synthesis, biological evaluation and SAR of novel benzimidazole derivatives as KOR agonists are described. The in vivo proof of principle for anti-nociceptive effect with a lead compound from this series is exemplified.",

author = "Sasmal, {Pradip K} and Krishna, {C Vamsee} and {Sudheerkumar Adabala}, S and Rawoof, {khaji Abdul} and Amima Thadi and Sukumar, {K Pawan} and Srisailam Cheera and Chandrasekhar Abbineni and Rao, {K V L Narasimha} and A Prasanthi and Kamal Nijhawan and Mahaboobi Jaleel and {Ramachandran Iyer}, Lakshmi and Chaitanya, {T Krishna} and Tiwari, {Nirbhay Kumar} and Krishna, {N Lavanya} and Vijay Potluri and Ish Khanna and Frimurer, {Thomas M} and Michael L{\"u}ckmann and {\O}ystein Rist and Lisbeth Elster and Thomas H{\"o}gberg",

year = "2015",

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doi = "10.1016/j.bmcl.2014.12.064",

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journal = "Bioorganic & Medicinal Chemistry Letters",

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T1 - Optimisation of in silico derived 2-aminobenzimidazole hits as unprecedented selective kappa opioid receptor agonists

AU - Sasmal, Pradip K

AU - Krishna, C Vamsee

AU - Sudheerkumar Adabala, S

AU - Rawoof, khaji Abdul

AU - Thadi, Amima

AU - Sukumar, K Pawan

AU - Cheera, Srisailam

AU - Abbineni, Chandrasekhar

AU - Rao, K V L Narasimha

AU - Prasanthi, A

AU - Nijhawan, Kamal

AU - Jaleel, Mahaboobi

AU - Ramachandran Iyer, Lakshmi

AU - Chaitanya, T Krishna

AU - Tiwari, Nirbhay Kumar

AU - Krishna, N Lavanya

AU - Potluri, Vijay

AU - Khanna, Ish

AU - Frimurer, Thomas M

AU - Lückmann, Michael

AU - Rist, Øystein

AU - Elster, Lisbeth

AU - Högberg, Thomas

PY - 2015/2/15

Y1 - 2015/2/15

N2 - Kappa opioid receptor (KOR) is an important mediator of pain signaling and it is targeted for the treatment of various pains. Pharmacophore based mining of databases led to the identification of 2-aminobenzimidazole derivative as KOR agonists with selectivity over the other opioid receptors DOR and MOR. A short SAR exploration with the objective of identifying more polar and hence less brain penetrant agonists is described herewith. Modeling studies of the recently published structures of KOR, DOR and MOR are used to explain the receptor selectivity. The synthesis, biological evaluation and SAR of novel benzimidazole derivatives as KOR agonists are described. The in vivo proof of principle for anti-nociceptive effect with a lead compound from this series is exemplified.

AB - Kappa opioid receptor (KOR) is an important mediator of pain signaling and it is targeted for the treatment of various pains. Pharmacophore based mining of databases led to the identification of 2-aminobenzimidazole derivative as KOR agonists with selectivity over the other opioid receptors DOR and MOR. A short SAR exploration with the objective of identifying more polar and hence less brain penetrant agonists is described herewith. Modeling studies of the recently published structures of KOR, DOR and MOR are used to explain the receptor selectivity. The synthesis, biological evaluation and SAR of novel benzimidazole derivatives as KOR agonists are described. The in vivo proof of principle for anti-nociceptive effect with a lead compound from this series is exemplified.

U2 - 10.1016/j.bmcl.2014.12.064

DO - 10.1016/j.bmcl.2014.12.064

M3 - Journal article

C2 - 25599839

SN - 0960-894X

VL - 25

SP - 887

EP - 892

JO - Bioorganic & Medicinal Chemistry Letters

JF - Bioorganic & Medicinal Chemistry Letters

IS - 4

ER -

Optimisation of in silico derived 2-aminobenzimidazole hits as unprecedented selective kappa opioid receptor agonists

Abstract

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