(1R,2S,4R,5S)-7-{[2-hydroxy-2,2-bis(thiophen-2-yl)acetyl]oxy}-9,9-dimethyl-3-oxa-9-azatricyclo[3.3.1.0^{2,4}]nonan-9-ium

• ChemBase ID: 1218
• Molecular Formular: C19H22NO4S2+
• Molecular Mass: 392.51228
• Monoisotopic Mass: 392.09902519
• SMILES: s1c(C(O)(C(=O)OC2C[C@H]3[N+]([C@H]([C@H]4O[C@@H]34)C2)(C)C)c2sccc2)ccc1
• Canonical SMILES: O=C(C(c1cccs1)(c1cccs1)O)OC1C[C@@H]2[C@H]3[C@@H]([C@H](C1)[N+]2(C)C)O3
• InChI: InChI=1S/C19H22NO4S2/c1-20(2)12-9-11(10-13(20)17-16(12)24-17)23-18(21)19(22,14-5-3-7-25-14)15-6-4-8-26-15/h3-8,11-13,16-17,22H,9-10H2,1-2H3/q+1/t11?,12-,13+,16+,17-
• InChIKey: LERNTVKEWCAPOY-KYQOMENCSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: (1R,2S,4R,5S)-7-{[2-hydroxy-2,2-bis(thiophen-2-yl)acetyl]oxy}-9,9-dimethyl-3-oxa-9-azatricyclo[3.3.1.0^{2,4}]nonan-9-ium
• IUPAC Traditional name: (1R,2S,4R,5S)-7-{[2-hydroxy-2,2-bis(thiophen-2-yl)acetyl]oxy}-9,9-dimethyl-3-oxa-9-azatricyclo[3.3.1.0^{2,4}]nonan-9-ium
• Brand Name: Spiriva
• Synonyms: Tiotropium bromide; Tiotropium

Database IDs

• CAS Number: 186691-13-4
• PubChem SID: 160964678; 46504448
• PubChem CID: 3086654; 3086655

CALCULATED PROPERTIES

JChem

• Acid pKa: 10.351076
• H Acceptors: 3
• H Donor: 1
• LogD (pH = 5.5): -1.7571676
• LogD (pH = 7.4): -1.7481594
• Log P: -1.7572837
• Molar Refractivity: 109.182 cm^3
• Polarizability: 38.91962 Å^3
• Polar Surface Area: 59.06 Å^2
• Rotatable Bonds: 5
• Lipinski's Rule of Five: true

ALOGPS 2.1

• Log P: -0.55
• LOG S: -4.44
• Solubility (Water): 1.56e-02 g/l

DETAILS

DrugBank - DB01409

• Drug Groups: approved
• Description: Tiotropium is a long-acting, 24 hour, anticholinergic bronchodilator used in the management of chronic obstructive pulmonary disease (COPD). Tiotropium is a muscarinic receptor antagonist, on topical application it acts mainly on M3 muscarinic receptors located in the airways to produce smooth muscle relaxation, thus producing a bronchodilatory effect.
• Indication: Used in the management of chronic obstructive pulmonary disease (COPD).
• Pharmacology: Tiotropium is a long–acting, antimuscarinic agent, which is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors, M1 to M5. In the airways, it exhibits pharmacological effects through inhibition of M3–receptors at the smooth muscle leading to bronchodilation. The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations. In preclinical in vitro as well as in vivo studies prevention of methacholine–induced bronchoconstriction effects were dose–dependent and lasted longer than 24 hours. The bronchodilation following inhalation of tiotropium is predominantly a site–specific effect.
• Toxicity: No mortality was observed at inhalation tiotropium doses up to 32.4 mg/kg in mice, 267.7 mg/kg in rats, and 0.6 mg/kg in dogs. These doses correspond to 7,300, 120,000, and 850 times the recommended human daily dose on a mg/m2 basis, respectively.
• Affected Organisms: Humans and other mammals
• Biotransformation: The extent of biotransformation appears to be small. This is evident from a urinary excretion of 74% of unchanged substance after an intravenous dose to young healthy volunteers. Tiotropium, an ester, is nonenzymatically cleaved to the alcohol N–methylscopine and dithienylglycolic acid, neither of which bind to muscarinic receptors. In vitro experiments with human liver microsomes and human hepatocytes suggest that a fraction of the administered dose (74% of an intravenous dose is excreted unchanged in the urine, leaving 25% for metabolism) is metabolized by cytochrome P450–dependent oxidation and subsequent glutathione conjugation to a variety of Phase II metabolites. Via inhibition studies, it is evident that CYP450 2D6 and 3A4 are involved in the metabolic pathway that is responsible for the elimination of a small part of the administered dose.
• Absorption: Bioavailability is 19.5% following administration by inhalation. Oral solutions of tiotropium have an absolute bioavailability of 2-3%.
• Half Life: 5-6 days
• Protein Binding: 72% bound to plasma proteins.
• Elimination: Intravenously administered tiotropium was mainly excreted unchanged in urine (74%). After dry powder inhalation, urinary excretion was 14% of the dose, the remainder being mainly non-absorbed drug in the gut which was eliminated via the feces.
• Distribution: * 32 L/kg
• Clearance: * 880 mL/min [young healthy volunteers receiving IV administration]; * Renal cl=326 mL/min [COPD patients (<58 years)]; * Renal cl=163 mL/min [COPD patients (>70 years)]
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