Pralnacasan

Synonyms :
HMR 3480

Status : investigational

Description

Pralnacasan is an orally bioavailable pro-drug of a potent, non-peptide inhibitor of interleukin-1beta converting enzyme (ICE).

Used

For the treatment of rheumatoid arthritis (RA).

Mechanism Of Action

Pralnacasan inhibits interleukin-1beta converting enzyme (ICE), an enzyme that regulates the production of IL-1 and IFN gamma – intercellular mediators that initiate and sustain the process of inflammation. Inhibiting ICE may be an effective strategy for curtailing damaging inflammatory processes common to a number of acute and chronic conditions, such as rheumatoid arthritis (RA) and osteoarthritis.

Pharmacodynamics

Pralnacasan is a potent, non-peptide inhibitor of interleukin-1beta converting enzyme (ICE). Pralnacasan is an oral, anti-cytokine drug candidate licensed for development by Aventis Pharma from Vertex Pharmaceuticals. In November 2003, Aventis and Vertex Pharmaceuticals announced that they had voluntarily suspended the phase II clinical trials of pralnacasan due to results from an animal toxicity study that demonstrated liver abnormalities after a nine-month exposure to pralnacasan at high doses. While no similar liver toxicity has been seen to date in human trials, the companies will evaluate the animal toxicity results before proceeding with the phase II clinical program.

Absorption

Orally bioavailable

Chemical Classification

This compound belongs to the class of organic compounds known as n-acyl-alpha amino acids and derivatives. These are compounds containing an alpha amino acid (or a derivative thereof) which bears an acyl group at its terminal nitrogen atom.

N-acyl-alpha amino acids and derivatives

Organic compounds

Organic acids and derivatives

Carboxylic acids and derivatives

Amino acids, peptides, and analogues

Chemical Name

HMR 3480

Calculated Property

kind Value Source
logP 0.16 ALOGPS
logS -3.1 ALOGPS
Water Solubility 3.87e-01 g/l ALOGPS
logP 0.07 ChemAxon
IUPAC Name N-[(4S,7S)-4-{[(2R,3S)-2-ethoxy-5-oxooxolan-3-yl]carbamoyl}-6,10-dioxo-octahydro-1H-pyridazino[1,2-a][1,2]diazepin-7-yl]isoquinoline-1-carboxamide ChemAxon
Traditional IUPAC Name N-[(4S,7S)-4-{[(2R,3S)-2-ethoxy-5-oxooxolan-3-yl]carbamoyl}-6,10-dioxo-hexahydro-1H-pyridazino[1,2-a][1,2]diazepin-7-yl]isoquinoline-1-carboxamide ChemAxon
Molecular Weight 523.5378 ChemAxon
Monoisotopic Weight 523.206698307 ChemAxon
SMILES CCO[C@@H]1OC(=O)C[C@@H]1NC(=O)[C@@H]1CCCN2N1C(=O)[C@H](CCC2=O)NC(=O)C1=NC=CC2=CC=CC=C12 ChemAxon
Molecular Formula C26H29N5O7 ChemAxon
InChI InChI=1S/C26H29N5O7/c1-2-37-26-18(14-21(33)38-26)29-23(34)19-8-5-13-30-20(32)10-9-17(25(36)31(19)30)28-24(35)22-16-7-4-3-6-15(16)11-12-27-22/h3-4,6-7,11-12,17-19,26H,2,5,8-10,13-14H2,1H3,(H,28,35)(H,29,34)/t17-,18-,19-,26+/m0/s1 ChemAxon
InChIKey InChIKey=CXAGHAZMQSCAKJ-WAHHBDPQSA-N ChemAxon
Polar Surface Area (PSA) 147.24 ChemAxon
Refractivity 131.03 ChemAxon
Polarizability 52.27 ChemAxon
Rotatable Bond Count 6 ChemAxon
H Bond Acceptor Count 7 ChemAxon
H Bond Donor Count 2 ChemAxon
pKa (strongest acidic) 12.26 ChemAxon
pKa (strongest basic) 1.49 ChemAxon
Physiological Charge 0 ChemAxon
Number of Rings 5 ChemAxon
Bioavailability 1 ChemAxon
Rule of Five 0 ChemAxon
Ghose Filter 0 ChemAxon
MDDR-Like Rule 1 ChemAxon

Affected organism

Humans and other mammals

Target within organism

  • Caspase-1 : in Human