Pyrazolopyrimidine inhibitors

PCI-32765 1 is the only Btk inhibitor which has been reported to have advanced to clinical trials [40]. Modeling of pyrazolopyrimidine 2 suggested that replacement of the cyclopentyl moiety could position an electrophilic group in proximity to Cys481, and subsequent optimization led to 1 [41]. Compound 1 inhibits Btk with an IC50 of 0.8 nM, and covalent binding to Btk was confirmed by mass spectrometry and washout experiments. In the Ramos B-cell line, 1 inhibits BCR-induced calcium... 

Other electrophilic substitution reactions on aromatic and heteroaromatic systems are summarized in Scheme 6.143. Friedel-Crafts alkylation of N,N-dimethyl-aniline with squaric acid dichloride was accomplished by heating the two components in dichloromethane at 120 °C in the absence of a Lewis acid catalyst to provide a 23% yield of the 2-aryl-l-chlorocydobut-l-ene-3,4-dione product (Scheme 6.143 a) [281]. Hydrolysis of the monochloride provided a 2-aryl-l-hydroxycyclobut-l-ene-3,4-dione, an inhibitor of protein tyrosine phosphatases [281], Formylation of 4-chloro-3-nitrophenol with hexamethylenetetramine and trifluoroacetic acid (TFA) at 115 °C for 5 h furnished the corresponding benzaldehyde in 43% yield, which was further manipulated into a benzofuran derivative (Scheme 6.143b) [282]. 4-Chloro-5-bromo-pyrazolopyrimidine is an important intermediate in the synthesis of pyrazolopyrimi-dine derivatives showing activity against multiple kinase subfamilies (see also Scheme 6.20) and can be rapidly prepared from 4-chloropyrazolopyrimidine and N-bromosuccinimide (NBS) by microwave irradiation in acetonitrile (Scheme... 

In addition to the preceding chemotypes, a limited number of patent specifications include PDKI as a target for the inhibitors exemplified in the cases. Thus, 5-aminocarbonylindazoles, pyrazolopyrimidines, triazolo[l,5-a]-pyrimidines, pyrazolopyrroles and phthalimides have been claimed to be active against PDKI [1], but further biological data are awaited. 

PPl (8) and its pyrazolopyrimidine analog PP2 (9) [99-108] were first described as potent inhibitors of SFKs with marked selectivity versus ZAP-70, JAK2, EGF-R, and PKA kinases. PPl provided an early key inhibitor of Src kinase to enable determination of its roles in VEGF-mediated angiogenesis and vascular permeability, Src-driven human breast cancer cell lines with respect to both heregulin-dependent or independent growth, and Src-related,... 

Zaleplon (Sonata) [C IV] [Sedotive/Hypnotic] Uses Insomnia Action A nonbenzodiazepine sedative/hypnotic, a pyrazolopyrimidine Dose 5-20 mg hs PRN -1- w/ renal/hepatic insuff, elderly Caution [C, /-] w/ mental/ psychological conditions Contra Component allergy Disp Caps SE HA, edema, amnesia, somnolence, photosens Interactions t CNS depression W/ CNS d es-sants, imipramine, thioridazine, EtOH X effects W/ carbamazepine, phenobarbital, phenytoin, rifampin EMS Concurrent EtOH can t adverse CNS effects OD May cause profound CNS depression symptomatic and supportive Zanamivir (Relenza) [Antiviral/Neuramidase Inhibitor] Uses Influenza A (including HlNl swine flu) B Action X Viral neuraminidase Dose Adults Feds > 7 y.2 inhal (10 mg) bid for 5 d initiate w/in 48 h of Sxs Caution [C, M] Contra Pulm Dz Disp Powder for inhal SE Bron-chospasm, HA, GI upset EMS Does not reduce risk of transmitting virus monitor for bronchospasm or other severe resp events OD May cause resp problems s5rmptomatic and supportive... 

Another pyrazolopyrimidine, formycin B, has been shown to be active against L. donovani (Table I) and L. mexicana. Carson and Chang demonstrated that this compound was phosphorylated to the ribonucleotide but was not converted to any APP ribonucleotides since it did not serve as a substrate for the adenylosuccinate synthetas, They did show that the ribonucleotide (FORB-MP) was an inhibitor of the adenylosuccinate synthetase. A more recent investigation has confirmed that donovani will convert formycin B to its ribonucleotide but also has shown that the latter is converted further to the APP ribonucleotides described above. This conversion was mediated by the adenylosuccinate synthetase at a slow rate. The kinetic constant for FORB-MP is high, compared to its natural substrate (K = 26uM),... 

What is the mechanism of this drug induced interference with pyrimidine metabolism The finding of orotic acid and orotidine in the urine is similar to that seen after therapy with the drug 6-azauridine. This compound is converted by a pyrimidine kinase to 6-azauridylic acid which competitively inhibits ODC (Handschumacher, 1960). By analogy a nucleotide derivative of allopurinol, oxipurinol or a metabolite may be a competitive inhibitor of ODC. In addition, a purine or pyrazolopyrimidine base could act as an inhibitor of OPRT or both mechanisms could work in concert. Finally, depletion of an essential substrate such as PP-ribose-P could also contribute. 

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