Prodrug derivatives of protein kinase C modulators

Patent metadata

Field	Value
Publication number	US-11370743-B2
Application number	US-201816604665-A
Country	US
Kind code	B2
Filing date	May 10, 2018
Priority date	May 12, 2017
Publication date	Jun 28, 2022
Grant date	Jun 28, 2022

Abstract

Embodiments of prodrugs of PKC modulators that show efficacy coupled with low levels of toxicity and improved stability are provided. The prodrug compounds are useful in academic research (animal studies), as candidates for preclinical research, and as therapeutic agents. By taking advantage of a pharmacophore-based strategy, this design strategy provides access to prodrugs of PKC modulators of diverse scaffolds including tigliane diterpenes, ingenane diterpenes, daphnane diterpene orthoesters, diacylglycerols, and bryostatins, and analogs thereof. In particular, embodiments of the prodrug ingenane esters having substitutions at C20 and their use as therapeutic agents are provided.

First claim

What is claimed:

1. A compound having the formula I:

wherein,
R 1 is a nonyl (C 9 H 19 ) group and R 2 is para-bromo-ortho-methylphenyl group.

2. A pharmaceutically acceptable composition comprising a protein kinase C (PKC) agonist prodrug, wherein the PKC agonist prodrug has the formula I:

wherein R 1 is a nonyl (C 9 H 19 ) group and R 2 is para-bromo-ortho-methylphenyl group,
and a pharmaceutically acceptable carrier.

3. A method of modulating the activity of a protein kinase C (PKC) in an animal or human cell comprising contacting an animal or human cell with a pharmaceutically acceptable composition comprising a PKC agonist prodrug having the formula I:

wherein R 1 is a nonyl (C 9 H 19 ) group and R 2 is para-bromo-ortho-methylphenyl group.

4. The method of claim 3 , wherein the pharmaceutically acceptable composition is administered to an animal or human subject.

5. The method of claim 3 , wherein the pharmaceutically acceptable composition is formulated for delivery to a patient in need thereof intravenously, intraparentally, subcutaneously, intramuscularly, orally, or by inhalation.

Assignees

• Univ Leland Stanford Junior

Inventors

• Wender Paul A
• Keenan Katherine N
• Benner Nancy Lynn
• Sloane Jack Leider
• Zang Xiaoyu

Classifications

• A61K9/0053

  Mouth and digestive tract, i.e. intraoral and peroral administration · CPC title

• C07C69/013 Primary

  Esters of alcohols having the esterified hydroxy group bound to a carbon atom of a ring other than a six-membered aromatic ring · CPC title

• C07C69/76 Primary

  Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring · CPC title

• C07C69/78

  Benzoic acid esters · CPC title

• A61K47/54

  the modifying agent being an organic compound · CPC title