Delving into the Latest Updates on AC10142A with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

CaM

Action

antagonists

Mechanism

CaM antagonists(Calmodulin antagonists)

Therapeutic Areas

Nervous System Diseases

Active Indication

Chronic PainInflammatory pain

Inactive Indication-

Originator Organization

Purdue University

Active Organization

Purdue University

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC18H21N5O

InChIKeyCAWNPHNPLIIGTM-ZDUSSCGKSA-N

CAS Registry2963581-29-3

Adenylyl cyclase isoform 1 (AC1) is considered a promising target for treating inflammatory pain. Our group identified the pyrazolyl-pyrimidinone scaffold as potent and selective inhibitors of Ca²⁺/CaM-mediated AC1 activity; however, the molecules suffered from poor aqueous solubility. The current study presents a strategy to improve aqueous solubility of the scaffold by reduction of crystal packing energy and increasing rotational degrees of freedom within the molecule. Structure-activity and property relationship studies identified the second generation lead 7-47A (AC10142A) that demonstrated and AC1 IC₅₀ value of 0.26 μM and aqueous solubility of 74 ± 7 μM. After in vitro ADME characterization, the scaffold advanced to in vivo pharmacokinetic evaluation, demonstrating adequate levels of exposure. Finally, 7-47A exhibited antiallodynic efficacy in a rat complete Freund's adjuvant model for inflammatory pain showing improvement over previous iterations of this scaffold. These results further validate AC1 inhibition as a viable therapeutic strategy for treating chronic and inflammatory pain.

100 Deals associated with AC10142A

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