Discovery of BMS-986308: A Renal Outer Medullary Potassium Channel Inhibitor for the Treatment of Heart Failure

Jeremy M. Richter; Prashantha Gunaga; Navnath Yadav; Rajesh Onkardas Bora; Rajeev Bhide; Nagendra Rajugowda; Kavitha Govindrajulu; Sreenivasulu Godesi; Nagarjuna Akuthota; Prasanna Rao; Aneesh Sivaraman; Manoranjan Panda; Mahammed Kaspady; Anuradha Gupta; Arvind Mathur; Paul C. Levesque; Jyoti Gulia; Manoj Dokania; Manjunath Ramarao; Prashant Kole; Silvi Chacko; Kimberley A. Lentz; Sankara Sivaprasad LVJ; Rajendra Prasad Thatipamula; Srikanth Sridhar; Shyam Kamble; Arun Govindrajan; Sharif I. Soleman; David A. Gordon; Ruth R. Wexler; E. Scott Priestley

doi:10.1021/acs.jmedchem.4c00893

Discovery of BMS-986308: A Renal Outer Medullary Potassium Channel Inhibitor for the Treatment of Heart Failure

Jeremy M. Richter, Prashantha Gunaga, Navnath Yadav, Rajesh Onkardas Bora, Rajeev Bhide, Nagendra Rajugowda, Kavitha Govindrajulu, Sreenivasulu Godesi, Nagarjuna Akuthota, Prasanna Rao, Aneesh Sivaraman, Manoranjan Panda, Mahammed Kaspady, Anuradha Gupta, Arvind Mathur, Paul C. Levesque, Jyoti Gulia, Manoj Dokania, Manjunath Ramarao, Prashant KoleSilvi Chacko, Kimberley A. Lentz, Sankara Sivaprasad LVJ, Rajendra Prasad Thatipamula, Srikanth Sridhar, Shyam Kamble, Arun Govindrajan, Sharif I. Soleman, David A. Gordon, Ruth R. Wexler, E. Scott Priestley

Department of Pharmacy

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

Recent literature reports highlight the importance of the renal outer medullary potassium (ROMK) channel in renal sodium and potassium homeostasis and emphasize the potential impact that ROMK inhibitors could have as a novel mechanism diuretic in heart failure patients. A series of piperazine-based ROMK inhibitors were designed and optimized to achieve excellent ROMK potency, hERG selectivity, and ADME properties, which led to the identification of compound 28 (BMS-986308). BMS-986308 demonstrated efficacy in the volume-loaded rat diuresis model as well as promising in vitro and in vivo profiles and was therefore advanced to clinical development.

Original language	English
Pages (from-to)	9731-9744
Number of pages	14
Journal	Journal of Medicinal Chemistry
Volume	67
Issue number	11
DOIs	https://doi.org/10.1021/acs.jmedchem.4c00893
State	Published - 13 Jun 2024

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Richter, J. M., Gunaga, P., Yadav, N., Bora, R. O., Bhide, R., Rajugowda, N., Govindrajulu, K., Godesi, S., Akuthota, N., Rao, P., Sivaraman, A., Panda, M., Kaspady, M., Gupta, A., Mathur, A., Levesque, P. C., Gulia, J., Dokania, M., Ramarao, M., ... Priestley, E. S. (2024). Discovery of BMS-986308: A Renal Outer Medullary Potassium Channel Inhibitor for the Treatment of Heart Failure. Journal of Medicinal Chemistry, 67(11), 9731-9744. https://doi.org/10.1021/acs.jmedchem.4c00893

@article{93894909d08448ea9a48f0e19afd7173,

title = "Discovery of BMS-986308: A Renal Outer Medullary Potassium Channel Inhibitor for the Treatment of Heart Failure",

abstract = "Recent literature reports highlight the importance of the renal outer medullary potassium (ROMK) channel in renal sodium and potassium homeostasis and emphasize the potential impact that ROMK inhibitors could have as a novel mechanism diuretic in heart failure patients. A series of piperazine-based ROMK inhibitors were designed and optimized to achieve excellent ROMK potency, hERG selectivity, and ADME properties, which led to the identification of compound 28 (BMS-986308). BMS-986308 demonstrated efficacy in the volume-loaded rat diuresis model as well as promising in vitro and in vivo profiles and was therefore advanced to clinical development.",

author = "Richter, {Jeremy M.} and Prashantha Gunaga and Navnath Yadav and Bora, {Rajesh Onkardas} and Rajeev Bhide and Nagendra Rajugowda and Kavitha Govindrajulu and Sreenivasulu Godesi and Nagarjuna Akuthota and Prasanna Rao and Aneesh Sivaraman and Manoranjan Panda and Mahammed Kaspady and Anuradha Gupta and Arvind Mathur and Levesque, {Paul C.} and Jyoti Gulia and Manoj Dokania and Manjunath Ramarao and Prashant Kole and Silvi Chacko and Lentz, {Kimberley A.} and {Sivaprasad LVJ}, Sankara and Thatipamula, {Rajendra Prasad} and Srikanth Sridhar and Shyam Kamble and Arun Govindrajan and Soleman, {Sharif I.} and Gordon, {David A.} and Wexler, {Ruth R.} and Priestley, {E. Scott}",

note = "Publisher Copyright: {\textcopyright} 2024 American Chemical Society",

year = "2024",

month = jun,

day = "13",

doi = "10.1021/acs.jmedchem.4c00893",

language = "English",

volume = "67",

pages = "9731--9744",

journal = "Journal of Medicinal Chemistry",

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Richter, JM, Gunaga, P, Yadav, N, Bora, RO, Bhide, R, Rajugowda, N, Govindrajulu, K, Godesi, S, Akuthota, N, Rao, P, Sivaraman, A, Panda, M, Kaspady, M, Gupta, A, Mathur, A, Levesque, PC, Gulia, J, Dokania, M, Ramarao, M, Kole, P, Chacko, S, Lentz, KA, Sivaprasad LVJ, S, Thatipamula, RP, Sridhar, S, Kamble, S, Govindrajan, A, Soleman, SI, Gordon, DA, Wexler, RR & Priestley, ES 2024, 'Discovery of BMS-986308: A Renal Outer Medullary Potassium Channel Inhibitor for the Treatment of Heart Failure', Journal of Medicinal Chemistry, vol. 67, no. 11, pp. 9731-9744. https://doi.org/10.1021/acs.jmedchem.4c00893

TY - JOUR

T1 - Discovery of BMS-986308

T2 - A Renal Outer Medullary Potassium Channel Inhibitor for the Treatment of Heart Failure

AU - Richter, Jeremy M.

AU - Gunaga, Prashantha

AU - Yadav, Navnath

AU - Bora, Rajesh Onkardas

AU - Bhide, Rajeev

AU - Rajugowda, Nagendra

AU - Govindrajulu, Kavitha

AU - Godesi, Sreenivasulu

AU - Akuthota, Nagarjuna

AU - Rao, Prasanna

AU - Sivaraman, Aneesh

AU - Panda, Manoranjan

AU - Kaspady, Mahammed

AU - Gupta, Anuradha

AU - Mathur, Arvind

AU - Levesque, Paul C.

AU - Gulia, Jyoti

AU - Dokania, Manoj

AU - Ramarao, Manjunath

AU - Kole, Prashant

AU - Chacko, Silvi

AU - Lentz, Kimberley A.

AU - Sivaprasad LVJ, Sankara

AU - Thatipamula, Rajendra Prasad

AU - Sridhar, Srikanth

AU - Kamble, Shyam

AU - Govindrajan, Arun

AU - Soleman, Sharif I.

AU - Gordon, David A.

AU - Wexler, Ruth R.

AU - Priestley, E. Scott

PY - 2024/6/13

Y1 - 2024/6/13

N2 - Recent literature reports highlight the importance of the renal outer medullary potassium (ROMK) channel in renal sodium and potassium homeostasis and emphasize the potential impact that ROMK inhibitors could have as a novel mechanism diuretic in heart failure patients. A series of piperazine-based ROMK inhibitors were designed and optimized to achieve excellent ROMK potency, hERG selectivity, and ADME properties, which led to the identification of compound 28 (BMS-986308). BMS-986308 demonstrated efficacy in the volume-loaded rat diuresis model as well as promising in vitro and in vivo profiles and was therefore advanced to clinical development.

AB - Recent literature reports highlight the importance of the renal outer medullary potassium (ROMK) channel in renal sodium and potassium homeostasis and emphasize the potential impact that ROMK inhibitors could have as a novel mechanism diuretic in heart failure patients. A series of piperazine-based ROMK inhibitors were designed and optimized to achieve excellent ROMK potency, hERG selectivity, and ADME properties, which led to the identification of compound 28 (BMS-986308). BMS-986308 demonstrated efficacy in the volume-loaded rat diuresis model as well as promising in vitro and in vivo profiles and was therefore advanced to clinical development.

UR - http://www.scopus.com/inward/record.url?scp=85194375486&partnerID=8YFLogxK

U2 - 10.1021/acs.jmedchem.4c00893

DO - 10.1021/acs.jmedchem.4c00893

M3 - Article

C2 - 38807539

AN - SCOPUS:85194375486

SN - 0022-2623

VL - 67

SP - 9731

EP - 9744

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 11

ER -

Discovery of BMS-986308: A Renal Outer Medullary Potassium Channel Inhibitor for the Treatment of Heart Failure

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