Transient receptor potential vanilloid-1 (TRPV1) antagonists such as A-1165442  have shown promising analgesic activity without the undesirable side effects of first-generation compounds. To expand our SAR knowledge in the isoquinoline urea series, additional isoquinoline ring substitution was desired. Utilizing three independent approaches, including an optimized propyne Sonagashira/NH-imine formation/cyclization cascade, a collection of trisubstituted isoquinolines was prepared. These were converted to a series of potent chromanurea TRPV1 antagonists which aptly demonstrated the effects of subtle structural changes on differential pharmacology.

Synthesis of trisubstituted isoquinoline TRPV1 antagonists

244th National Meeting (2012)

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