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Novel Autotaxin Inhibitors for the Treatment of Osteoarthritis Pain: Lead Optimization via Structure-Based Drug Design.

ABSTRACT: In an effort to develop a novel therapeutic agent aimed at addressing the unmet need of patients with osteoarthritis pain, we set out to develop an inhibitor for autotaxin with excellent potency and physical properties to allow for the clinical investigation of autotaxin-induced nociceptive and neuropathic pain. An initial hit identification campaign led to an aminopyrimidine series with an autotaxin IC50 of 500 nM. X-ray crystallography enabled the optimization to a lead compound that demonstrated favorable potency (IC50 = 2 nM), PK properties, and a robust PK/PD relationship.

SUBMITTER: Jones SB

PROVIDER: S-EPMC5018868 | biostudies-other | 2016 Sep

REPOSITORIES: biostudies-other

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Novel Autotaxin Inhibitors for the Treatment of Osteoarthritis Pain: Lead Optimization via Structure-Based Drug Design.

Jones Spencer B SB Pfeifer Lance A LA Bleisch Thomas J TJ Beauchamp Thomas J TJ Durbin Jim D JD Klimkowski V Joseph VJ Hughes Norman E NE Rito Christopher J CJ Dao Yen Y Gruber Joseph M JM Bui Hai H Chambers Mark G MG Chandrasekhar Srinivasan S Lin Chaohua C McCann Denis J DJ Mudra Daniel R DR Oskins Jennifer L JL Swearingen Craig A CA Thirunavukkarasu Kannan K Norman Bryan H BH

ACS medicinal chemistry letters 20160802 9

In an effort to develop a novel therapeutic agent aimed at addressing the unmet need of patients with osteoarthritis pain, we set out to develop an inhibitor for autotaxin with excellent potency and physical properties to allow for the clinical investigation of autotaxin-induced nociceptive and neuropathic pain. An initial hit identification campaign led to an aminopyrimidine series with an autotaxin IC50 of 500 nM. X-ray crystallography enabled the optimization to a lead compound that demonstra ...[more]

PMID: 27660691

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