194423-06-8

Basic information

• Product Name: 2-ButynaMide, N-[4-[(3-broMophenyl)aMino]-6-quinazolinyl]-
• Synonyms: 2-ButynaMide, N-[4-[(3-broMophenyl)aMino]-6-quinazolinyl]-;CL-387785 (EKI-785);N-(4-(3-bromophenylamino)quinazolin-6-yl)but-2-ynamide;N-[4-[(3-broMophenyl)aMino]-6-quinazolinyl]-2-ButynaMide CL-387785;CL-387785, >=98%;CL-38875;EKB 785;WAY-EKI 785
• CAS NO: 194423-06-8
• Molecular Formula: C₁₈H₁₃BrN₄O
• Molecular Weight: 381.22602
• Product Categories: Inhibitors
• Mol File: 194423-06-8.mol
• Article Data: 10

Chemical Properties

• Melting Point: 276 °C
• Appearance: /
• Density: 1.577±0.06 g/cm3(Predicted)
• Storage Temp.: Sealed in dry,Store in freezer, under -20°C
• Solubility: insoluble in EtOH; insoluble in H2O; ≥16.85 mg/mL in DMSO
• PKA: 9.84±0.43(Predicted)
• CAS DataBase Reference: 2-ButynaMide, N-[4-[(3-broMophenyl)aMino]-6-quinazolinyl]-(CAS DataBase Reference)
• NIST Chemistry Reference: 2-ButynaMide, N-[4-[(3-broMophenyl)aMino]-6-quinazolinyl]-(194423-06-8)
• EPA Substance Registry System: 2-ButynaMide, N-[4-[(3-broMophenyl)aMino]-6-quinazolinyl]-(194423-06-8)

Safety Data

• Hazardous Substances Data: 194423-06-8(Hazardous Substances Data)

Usage

Pharmacological activity

Overactivity of epidermal growth factor receptor (EGFR) tyrosine kinase activity has been associated with a number of cancers.CL 387,785 profoundly blocks the growth of EGFR-overexpressing tumors in nude mice when given orally at 80 mg/kg/day for 10 days.

Description

Overactivity of epidermal growth factor receptor (EGFR) tyrosine kinase activity has been associated with a number of cancers. CL 387,785 is a potent, irreversible inhibitor of EGFR kinase activity (IC50 = 370 pM). It blocks EGF-stimulated autophosphorylation of receptors in cells (IC50 = 5 nM) and halts cell cycling in cells that overexpress EGFR or c-ErbB2 (IC50s = 31-125 nM). CL 387,785 profoundly blocks the growth of EGFR-overexpressing tumors in nude mice when given orally at 80 mg/kg/day for 10 days.

Uses

CL-387785 (EKI-785) is an irreversible and selective EGFR inhibitor showing activity against mutations of the receptor. Potential therapeutic against various type of cancer, including lung cancer.

Definition

ChEBI: A member of the class of quinazolines that is 4,6-diaminoquinazoine in which the one of the hydrogens attached to the amino group at position 4 has been replaced by a m-bromophenyl group while one of the hydrogens attached to the amino group a position 6 has been replaced by a but-2-ynoyl group.

in vitro

cl-387785 covalently bound to egfr. it also specifically inhibited kinase activity of the protein, blocked egf-stimulated autophosphorylation of the receptor in cells, inhibited cell proliferation primarily in a cytostatic manner in cell lines that overexpress egf-r or c-erbb-2 [1].

in vivo

the effects of cl-387785 on tumor growth were assessed in human tumor xenografts implanted s.c. in the flanks of nude mice. cl-387785 inhibited the growth of tumors derived from a431 cells when the drug was administered i.p. or p.o.. inhibitory effects were observed within 7 days after the onset of therapy. no efficacy was observed with cl-387785 in tumors derived from cell lines that did not overexpress egf-r, including the human breast carcinoma mda-mb-435 [1].

IC 50

370 pm

references

[1] discafani cm, carroll ml, floyd mb jr, hollander ij, husain z, johnson bd, kitchen d, may mk, malo ms, minnick aa jr, nilakantan r, shen r, wang yf, wissner a, greenberger lm. irreversible inhibition of epidermal growth factor receptor tyrosine kinase with in vivo activity by n-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide (cl-387,785). biochem pharmacol. 1999 apr 15;57(8):917-25.

Upstream product

• 194423-18-2 but-2-ynoic acid [3-cyano-4-(dimethylamino-methyleneamino)-phenyl]-amide 
• 591-19-5 m-Bromoaniline 
• 109-02-4 4-methyl-morpholine 
• 590-93-2 2-Butynoic acid 
• 169205-78-1 6-amino-4-[(3-bromophenyl)amino]quinazoline 
• 543-27-1 isobutyl chloroformate 
• 208533-38-4 [4-chloro-6-quinazolinyl]-2-butynamide 
• 169205-77-0 6-nitro-4-(3-bromophenylaniline)quinazoline 
• 17420-30-3 5-nitroanthranilonitrile 

Relevant articles and documents

Tyrosine kinase inhibitors. 19. 6-alkynamides of 4-anilinoquinazolines and 4-anilinopyrido[3,4-d]pyrimidines as irreversible inhibitors of the erbB family of tyrosine kinase receptors

Structure-activity relationships for inhibition of erbB1, erbB2, and erbB4 were determined for a series of alkynamide analogues of quinazoline- and pyrido[3,4-ui]pyrimidine-based compounds. The compounds were prepared by coupling the appropriate 6-aminoquinazolines or 6-aminopyrido[3,4-d]pyrimidines with alkynoic acids, using EDCI·HCl in pyridine. The compounds showed pan-erbB enzyme inhibition but were on average about 10-fold more potent against erbB1 than against erbB2 and erbB4. For cellular inhibition, the nature of the alkylating side chains was an important determinant, with 5-dialkylamino-2- pentynamide type Michael acceptors providing the highest potency. This is suggested to be due to an improved ability of the amine to participate in an autocatalysis of the Michael reaction with enzyme cysteine residues. Pyrido[3,4-d]pyrimidine analogue 39 was selected for in vivo evaluation and achieved tumor regressions at 10 mg/kg in the A431 human epidermoid carcinoma and at 40 mg/kg for the SF767 human glioblastoma and the SKOV3 human ovarian carcinoma. Complete stasis was observed at 40 mg/kg in the BXPC3 human pancreatic carcinoma as well as in the H125 human non-small-cell lung carcinoma.

USE OF QUINAZOLINE COMPOUNDS FOR THE TREATMENT OF POLYCYSTIC KIDNEY DISEASE

This invention provides a method of treating or inhibiting polycystic kidney disease in a mammal in need thereof which comprises administering to said mammal a compound having formula (1) wherein X is phenyl which is optionally substituted; R and R1 are each, independently, hydrogen, halogen, alkyl, alkoxy, hydroxy, or trifluoromethyl; R2 is hydrogen, alkyl, alkoxy, hydroxy, trifluoromethyl; Y is a radical selected from the group consisting of (a), (b), (c), (d), (e), (f) and (g); R3 is independently hydrogen, alkyl, carboxy, carboalkoxy, phenyl, or carboalkyl; n = 2-4; or a pharmaceutically acceptable salt thereof, with the proviso that each R3 of Y may be the same or different.

Method of treating or inhibiting colonic polyps

This invention provides a method of treating or inhibiting colonic polyps in a mammal in need thereof which comprises administering to said mammal a compound having the formula wherein:X is phenyl which is optionally substituted;R and R1 are each, independently, hydrogen, halogen, alkyl, alkoxy, hydroxy, or trifluoromethyl;R2 is hydrogen, alkyl, alkoxy, hydroxy, trifluoromethyl;Y is a radical selected from the group consisting of R3 is independently hydrogen, alkyl, carboxy, carboalkoxy, phenyl, or carboalkyl;n=2-4;or a pharmaceutically acceptable salt thereof, with the proviso that each R3 of Y may be the same or different.