Steven P. Seitz

Quinazolines as cyclin dependent kinase inhibitors.

Quinazolines have been identified as inhibitors of CDK4/D1 and CDK2/E. Aspects of the SAR were investigated using solution-phase, parallel synthesis. An X-ray crystal structure was obtained of quinazoline 51 bound in CDK2 and key interactions within the ATP binding pocket are defined.

Synthesis and evaluation of analogs of Efavirenz (SUSTIVATM) as HIV-1 reverse transcriptase inhibitors

Abstract Efavirenz (SUSTIVA TM ) is a potent non-nucleoside reverse transcriptase inhibitor. Due to the observation of breakthrough mutations of the reverse transcriptase enzyme during Efavirenz therapy, we sought to develop an optimized second generation series. To that end, SAR of the substituents on the aromatic ring was undertaken and the results are summarized here. The 5,6-difluoro ( 4f ) and the 6-methoxy ( 4m ) substituted benzoxazinones were determined to be equipotent, and as a result such substitution patterns will be incorporated in second generation scaffolds.

Identification of selective inhibitors of cyclin dependent kinase 4

A new structural type of kinase inhibitor, containing a benzocarbazole nucleus, has been identified. Members of the series are selective for inhibition of the cyclin dependent kinase family of enzymes. Although the cdks are highly homologous, representatives of the series showed intra-cdk selectivities, especially for cdk4. SAR studies elucidated the important features of the molecules for inhibition.

Design and selection of DMP 850 and DMP 851: the next generation of cyclic urea HIV protease inhibitors

Abstract Background: Recent clinical trials have demonstrated that HIV protease inhibitors are useful in the treatment of AIDS. It is necessary, however, to use HIV protease inhibitors in combination with other antiviral agents to inhibit the development of resistance. The daunting ability of the virus to rapidly generate resistant mutants suggests that there is an ongoing need for new HIV protease inhibitors with superior pharmacokinetic and efficacy profiles. In our attempts to design and select improved cyclic urea HIV protease inhibitors, we have simultaneously optimized potency, resistance profile, protein binding and oral bioavailability. Results: We have discovered that nonsymmetrical cyclic ureas containing a 3-aminoindazole P2 group are potent inhibitors of HIV protease with excellent oral bioavailability. Furthermore, the 3-aminoindazole group forms four hydrogen bonds with the enzyme and imparts a good resistance profile. The nonsymmetrical 3-aminoindazoles DMP 850 and DMP 851 were selected as our next generation of cyclic urea HIV protease inhibitors because they achieve 8 h trough blood levels in dog, with a 10 mg/kg dose, at or above the protein-binding-adjusted IC 90 value for the worst single mutant — that containing the Ile84→4Val mutation. Conclusions: In selecting our next generation of cyclic urea HIV protease inhibitors, we established a rigorous set of criteria designed to maximize chances for a sustained antiviral effect in HIV-infected individuals. As DMP 850 and DMP 851 provide plasma levels of free drug that are sufficient to inhibit wild-type HIV and several mutant forms of HIV, they could show improved ability to decrease viral load for clinically significant time periods. The ultimate success of DMP 850 and DMP 851 in clinical trials might depend on achieving or exceeding the oral bioavailability seen in dog.

Synthesis and biological activities of potential metabolites of the non-nucleoside reverse transcriptase inhibitor Efavirenz

Studies on the biotransformation of the clinically important non-nucleoside reverse transcriptase inhibitor efavirenz have shown that oxidation and secondary conjugation are important components of the processing of this molecule in vivo. We have synthesized metabolites of efavirenz to confirm their structure and to evaluate their activity as antivirals.

The synthesis and evaluation of cyclic ureas as hiv protease inhibitors : Modifications of the P1/P1' residues

Two series of cyclic ureas modified at the P1/P1 residue were prepared and evaluated for HIV protease inhibition and whole cell antiviral activity. Compounds 8b, 10 (3- and 4-pyridylmethyl analogs) and 6b (4-methoxy analog) showed significant improvement in antiviral activity relative to lead compounds DMP323 and DMP 450.

The synthesis of symmetrical and unsymmetrical P1/P1' cyclic ureas as HIV protease inhibitors.

Cyclic urea SD146, a potent HIV protease inhibitor bearing a flat resistance profile, possessed poor solubility and bioavailability, which precluded further development of the compound. In an effort to improve upon the pharmacokinetic profile of the compound, several analogs modified at the P1/P1 residues were prepared and evaluated. Several of those compounds displayed significant improvement of physical properties.

The synthesis and antitumor evaluation of unsymmetrical bis-imides

Unsymmetrical bis-imides 1 were synthesized and evaluated as potential antitumor agents. These novel bis-imides were assessed using three criteria: in vitro cytotoxicity (L1210), in vitro DNA binding, and in vivo studies with human tumor xenografts in mice. These studies identified DMP 315 as a potent, water soluble antitumor agent.

Increased antiviral activity of cyclic urea HIV protease inhibitors by modifying the P1/P1' substituents.

A series of alkyl substituted P1/P1 analogs was prepared in an attempt to increase translation of the 3-aminoindazole class of HIV protease inhibitors. Increasing the lipophilicity of the P1/P1 residues dramatically improved translation of enzyme activity to antiviral activity in the whole cell assay.

Functionalized aliphatic P2/P2' analogs of HIV-1 protease inhibitor DMP323

Abstract A series of analogs of HIV protease inhibitor DMP323 containing functionalized aliphatic P2/P2′ groups was prepared and evaluated for HIV protease inhibition and antiviral activity in a cell-based assay. Asymmetric compounds with a 5-hydroxypentyl substituent at P2 and a benzylic substituent at P2′ showed increased potency over the corresponding symmetrically substituted analogs.