These novel substituted piperidine and piperazine pyrazoles are designed to block the CYP4-mediated conversion of arachidonic acid to 20-HETE by integrating an aryl or heteroaryl moiety (X) through a linking group (Y) to a nitrogen or CH unit (Z) on a piperidine or piperazine core bearing a pyrazolyl substituent (R1). They exhibit low nanomolar IC50 values in human, rat, and rabbit liver microsomes, high aqueous solubility, and excellent metabolic stability (low intrinsic clearance). In vitro assays using MDR1-MDCK monolayers demonstrate high apical-to-basolateral permeability and low efflux ratios, indicating favorable blood–brain barrier penetration. The compounds are assembled via Ullmann or Buchwald–Hartwig coupling of protected halogenated pyrazoles with substituted piperidines/piperazines, followed by deprotection to yield the active inhibitors.
Description
These molecules stand out from earlier 20-HETE formation blockers—such as long-chain fatty acid mimics and suicide inhibitors—by achieving a balance of potency, solubility, stability, and central nervous system access. Unlike previous agents that suffer from high lipophilicity, rapid clearance, poor selectivity, and limited half-life, these pyrazole derivatives deliver enhanced enzyme affinity, improved physicochemical profiles, and robust microsomal resistance. Their optimized permeability and low efflux further distinguish them as promising candidates for neuroprotective and renal therapies.
Applications
- Acute ischemic stroke therapy
- Subarachnoid hemorrhage treatment
- Polycystic kidney disease therapy
- Traumatic brain injury treatment
- Post-cardiac arrest neuroprotection
Advantages
- High potency inhibition of CYP4-mediated 20-HETE formation (low IC₅₀ in human, rat, and rabbit microsomes)
- Enhanced aqueous solubility for improved formulation and bioavailability
High metabolic stability (low intrinsic clearance in liver microsomes)
- Favorable blood–brain barrier penetration (high apical-to-basolateral permeability, low efflux ratio)
- Selective targeting of CYP4 enzymes, reducing off-target activity
IP Status
https://patents.google.com/patent/WO2020163689A1
