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A series of 3-[6-(4-substituted-piperazin-1-yl)-4-methyl-1H-benzimidazol-2-yl]-1H-pyridine-2-one were synthesized to modulate CYP3A4 inhibition and improve aqueous solubility of our prototypical compound BMS-536924 (1), while maintaining potent IGF-1R inhibitory activity. Structure-activity and structure-solubility studies led to the identification of BMS-577098 (27), which demonstrates oral in vivo efficacy in animal models. The improvement was achieved by replacing morpholine with more polar bio-isoster piperazine and modulating the basicity of distal nitrogen with appropriate substitutions.

Generation of imino-quinone methide type intermediates from 2-aminothiazole-5-carbinols using alkylsulfonic acids in nitromethane followed by trapping with a wide range of nucleophiles effects C-C, C-O, C-N, C-S, and C-P bond formation.

3-(Benzimidazol-2-yl)-pyridine-2-one-based ATP competitive inhibitors of Insulin-like Growth Factor 1 Kinase (IGF-IR) were optimized for reduced Cyp3A4 inhibition and improved oral exposure. The use of malonate as methyl anion synthon via S(N)Ar reaction and double decarboxylation under mild conditions is demonstrated.

Pyrrolotriazine dual EGFR/HER2 kinase inhibitors with a 5-((4-aminopiperidin-1-yl)methyl) solubilizing group were found to be superior to analogs with previously reported C-5 solubilizing groups. New synthetic methodology was developed for the parallel synthesis of C-4 analogs with the new solubilizing group. Interesting new leads were evaluated in tumor xenograft models and the C-4 aminofluorobenzylindazole, 1c, was found to exhibit the best antitumor activity. It is hypothesized that this solubilizing group extends into the ribose-phosphate portion of the ATP binding pocket and enhances the binding affinity of the inhibitor.

A series of 3-(1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-one inhibitors of insulin-like growth factor receptor-1 (IGF-1R) were examined in which the pendant imidazole moiety was replaced to improve selectivity for IGF-1R inhibition over cytochrome P450 (CYP). Synthesis and SAR of these compounds is presented.

The discovery and synthesis of 3-(1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-one inhibitors of insulin-like growth factor 1-receptor (IGF-1R) are presented. Installing amine containing side chains at the 4-position of pyridone ring significantly improved the enzyme potency. SAR and biological activity of these compounds is presented.

Novel C-5 substituted pyrrolotriazines were optimized for dual EGFR and HER2 protein tyrosine kinase inhibition. The lead compound exhibited promising oral efficacy in both EGFR and HER2 driven human tumor xenograft models. It is hypothesized that its C-5 morpholine side chain binds in the ribose phosphate portion of the ATP binding pocket.

We have recently identified BMS-345541 (1) as a highly selective and potent inhibitor of IKK-2 (IC50 = 0.30 μM), which however was considerably less potent against IKK-1 (IC50 = 4.0 μM). In order to further explore the SAR around the imidazoquinoxaline tricyclic structure of 1, we prepared a series of tetracyclic analogues (7, 13, and 18). The synthesis and biological activities of these potent IKK inhibitors are described.

A novel class of 1H-(benzimidazol-2-yl)-1H-pyridin-2-one inhibitors of insulin-like growth factor I (IGF-1R) kinase is described. This report discusses the SAR of 4-(2-hydroxy-2-phenylethylamino)-substituted pyridones with improved IGF-1R potency.

Pyrrolotriazines with an ester group at C-5 were prepared and evaluated as inhibitors of the EGFR and HER2 receptor tyrosine kinases, validated targets for cancer therapy. The C-5 ester (15) was at least as potent as its C-6 ester analogue (17), an example of a known series of pyrrolotriazine EGRF/HER2 kinase inhibitors that show good biochemical and cellular activity. The C-5 esters were synthesized from pyrrole 2,3-diesters that were made by a new, one-pot procedure. This involved reaction of readily available N-tosyl derivatives of α-amino acid esters or ketones with triphenylphosphine and diethyl acetylenedicarboxylate to form 3-pyrrolines via an intramolecular Wittig olefination. The 3-pyrroline intermediates were not isolated but treated directly with base to eliminate toluenesulfinic acid and generate the pyrrole 2,3-diesters in good yield.Key words: pyrrolotriazine, EGFR, HER2, pyrrole, intramolecular Wittig reaction.

A series of fluoroglycosylated fluoroindolocarbazoles was examined with respect to their topoisomerase I activity, cytotoxicity, and selectivity. The lead clinical candidate from this series, BMS-250749, displays broad spectrum antitumor activity superior to CPT-11 against some preclinical xenograft models, including curative antitumor activity against Lewis lung carcinoma.

The evolution of 2, a C-4-methylcarbonate analogue of paclitaxel with minimal oral bioavailability and oral efficacy, into its C-3'-t-butyl-3'-N-t-butyloxycarbonyl analogue (15i), a novel taxane with oral efficacy in preclinical models that is comparable to iv administered paclitaxel, is described.

The synthesis and biological activity of sordarin oxazepine derivatives are described. The key step features a regioselective oxidation of an unprotected triol followed by double reductive amination to afford the ring-closed products. The spectrum of antifungal activity for these novel derivatives includes coverage of Candida albicans, Candida glabrata, and Cryptococcus neoformans.

A fermentation directed product search for potential anticancer drugs conducted by Bristol-Myers in the 1970s and early 1980s resulted in the identification of a novel indolocarbazole (IC) rebeccamycin (RBM) as a potential drug development candidate. Subsequently, an analog program designed to impart distal site in vivo antitumor activity resulted in the discovery of diethylaminoethyl analog of RBM (DEAE-RBM), which is presently undergoing clinical evaluation as NSC 655649 and BMY-27557. Strong DNA intercalation is the primary mechanism of action of DEAE-RBM resulting in the potent catalytic inhibition of both topoisomerases I and II. Precursor feeding fermentation experiments with fluorine-substituted tryptophans yielded novel fluoroindolocarbazoles (FICs). These FICs were identified as targeting topoisomerase (topo) I in a mechanism-based screen and their action on topo I was confirmed by production of topo I-mediated single-strand breaks in DNA at sites essentially identical to those induced by camptothecin. Topo I dependent cytotoxicity was demonstrated for specific FICs using a P388 and camptothecin-resistant P388/CPT45 pair of cell lines, the latter expresses little or no functional topo I. For example, topo I selectivity was greatest with 3,9-difluoro substituted FIC and was least significant and least cytotoxic with 4,8-difluoro substituted FIC. The review focuses on the discovery of the rebeccamycin class of compounds and their structure-activity relationships leading to the development of the clinical candidate BMY-27557 (NSC 655649), as well as the lead identification of the fluoroindolocarbazole class of compounds.

[structure: see text] 2-Aryl-2,2-difluoroacetamido-proline and pipecolate esters are high affinity FKBP12 ligands whose rotamase inhibitory activity is comparable to that seen for the corresponding ketoamides. X-ray structural studies suggest that the fluorine atoms participate in discrete interactions with the Phe36 phenyl ring and the Tyr26 hydroxyl group, with the latter resembling a moderate-to-weak hydrogen bond.

The syntheses and antitumor activity of three paclitaxel-chlorambucil hybrids are presented. Hybrid 3 showed significant in vivo efficacy.

The synthetic transposition of the 7-hydroxyl group of paclitaxel to the 6-position is described. The route presented prepares both the 6-α- and β-isomers stereospecifically. The key step of this transposition involves the stereoselective reduction of the 6,7-α-thiocarbonate using tributylgermanium hydride.

An efficient syntheses of the 3′-N isomeric paclitaxel analogs, 4 and 5, are described. A highly diastereoselective Sharpless asymmetric dihydroxylation reaction is utilized to establish the required (2′R,3′S) stereochemistry on the C-13 side chain. Both of the 3′-N modified analogs 4 and 5 were found to be cytotoxic in vitro. Analog 4 also displayed comparable in vivo activity to that of paclitaxel in the ip M-109 tumor model.

An esperamicin core analog 4 with an epoxide trigger like that found in the related enediyne, dynemicin, was prepared. Surprisingly, it was found to be relatively stable; the p -aminophenyl substituent did not facilitate epoxide solvolysis to the extent that had been anticipated. A mild acid, pyridinium p -toluenesulfonate, was found to induce solvolysis of 4 and led to the formation of the cycloaromatized product 25 .

An enediyne analog ( 2 , R=H) that is a hybrid of the core structures of esperamicin and dynemicin was prepared. The key step in its synthesis was a Reissert-type reaction that involved intramolecular addition of the anion of a Z-1,3-diyn-2-ene to an N-acyl tetrahydrophenathridinium intermediate. It was found that 2 (R=H) readily undergoes epoxide rearrangement to an allylic alcohol ( 16 ). Both 2 (R=H) and 16 form the same cycloaromatized product 17 when heated in MeOH at 45 °C.

Synthesis and cytotoxicity properties of novel C-2′ analogues of paclitaxel are described. The analogues were synthesized using Holton's β-lactam approach to append the side chain on baccatin III. The key intermediate to the synthesis of novel analogues was prepared employing an unprecedented stereocontrolled addition of Grignard reagent to a chiral azetidine-2,3-dione.

The synthesis, pharmacokinetic properties, and antitumor evaluation of novel paclitaxel phosphonooxymethyl ether derivatives 8–11 and salts thereof is described. These compounds exhibit improved water solubility as compared to paclitaxel (1) and upon incubation with plasma and alkaline phosphatase they readily release parent drug. The in vivo antitumor evaluation of compounds 8–11 established them as suitable pro-drugs of paclitaxel.

A large number of C-4 paclitaxel analogs have been prepared in the course of our systematic C-4 modification. These include C-4 esters, carbonates, carbamates as well as a C-4 deacetyl derivative. All of these analogs were evaluated in a tubulin polymerization assay as well as in a cytotoxicity assay against a human colon cancer cell line. The potent analogs emerging from these in vitro assays were further evaluated in vivo. With the exception of paclitaxel side chain bearing C-4 carbamates and C-4 aromatic esters, most of the C-4 aliphatic esters and carbonates were found to possess comparable or superior activity to paclitaxel in vitro. Several C-4 aliphatic esters and carbonates also exhibited in vivo activities against i.p. implanted murine M-109 lung carcinoma.

Three new phosphate derivatives of paclitaxel-2′-ethylcarbonate 4a, 4b, and 4c, have been synthesized and evaluated for in vivo antitumor activity. All were soluble in water and two derivatives 4a and 4b were found to exhibit in vivo antitumor activity, comparable to paclitaxel in the M109 murine tumor model.

The thiol activation and aromatization of bicyclo[7.1.0]enediynes was found to be dependent of the nature of the propargyl substituent. These effects are correlated to antitumor activity.

Etoposide Phosphate (BMY-40481) is synthesized semisynthetically from the clinically approved anticancer parent drug, etoposide (VP-16-213), and also from natural (−)-epipodophyllotoxin. Etoposide phosphate functions as a clinically active, water soluble prodrug of etoposide. The NDA for etoposide phosphate was filed in June, 1994.

A series of taxol derivatives, modified at C-7, is described. This includes sulfonate, silylether, ester, carbonate, carbamate, fluoro, dehydro and deoxy derivatives. Biological evaluation shows that these modifications do not usually significantly compromise activity. However, none of the C-7 analogs prepared thus far have been shown to be better than taxol in both in vitro and in vivo assays.

A chemoselective approach to functionalize the C-10 position of 10-deacetyl baccatin III, a key intermediate for the semi-synthesis of paclitaxel, is described. The chemistry provides an easy access to a variety of C-10 hydroxyl derivatives, such as, ethers, esters, carbonates, carbamates, and sulfonates under mild conditions. The C-10 modified baccatin derivatives were further employed in the synthesis of novel biologically active Taxol® analogues.

Red-Al was used to selectively remove the C 2 benzoate of 7,13-bisTES baccatin ( 8 ). Derivatization of the resulting C 2 hydroxy compound provided the corresponding p-nitrophenyl carbamate, the p-methoxy and p-nitrobenzoates, and cyclohexyl ester. Attachment of the taxol side chain to the above four analogs via lactam ( 15 ) followed by desilylation provided five analogs of taxol modified at the C 2 position, including a C 1,2 cyclic carbonate. These five analogs were less potent than taxol in a tubulin polymerization assay and a cytotoxicity assay against human colon cancer cell line.

Core-modified sordaricin derivatives were prepared via biotransformation followed by chemical modification and tested for antifungal activity. The antifungal activity proved to be very sensitive to modifications in the sterics and/or lipophilicity of the diterpene skeleton. Introduction of polar groups such as hydroxyl in the diterpene core results in loss of potency while small and lipophilic groups such as fluorine and the 7,8-olefin are well tolerated.

Therapeutic development of a targeted agent involves a series of decisions over additional activities that may be ignored, eliminated or pursued. This paper details the concurrent application of two methods that provide a spectrum of information about the biological activity of a compound: biochemical profiling on a large panel of kinase assays and transcriptional profiling of mRNA responses. Our mRNA profiling studies used a full dose range, identifying subsets of transcriptional responses with differing EC(50)s which may reflect distinct targets. Profiling data allowed prioritization for validation in xenograft models, generated testable hypotheses for active compounds, and informed decisions on the general utility of the series.

Analogues of taxol with a modified phenylisoserine side chains were synthesized and evaluated as potential cytotoxic agents.

The E-ring 3′,4′,5′-trihydroxy etoposide analog 3 of the clinical antitumor agent etoposide 1 was synthesized from the corresponding etoposide ortho-quinone 2 . This analog is twice as potent as etoposide in its ability to elicit topoisomerase II mediated DNA double strand breaks. However, our in vitro cytotoxicity assay, using human colon tumor cells grown in culture, and our in vivo P388 murine leukemia screen reveal considerable loss of potency and/or activity vis-a-vis etoposide.

Synthesis and biological evaluation of novel taxol derivatives having a phosphonoxyphenylpropionate ester group at the 2′-position or at the 7-position of taxol are described. These were found to have much improved water solubility and both were found to generate taxol upon exposure to alkaline phosphatase. A particular derivative, 7-phosphonoxyphenylpropionate of taxol 3b exhibited antitumor activity comparable to that of taxol against the ip/ip M109 murine tumor model.

The simple enediyne core molecule 1 is shown to cause protein damage to several cellular protein isolates in vitro. The aromatization of 1 to generate a benzene diradical under simulated physiological conditions is also described.

Synthesis and in vivo antitmor evaluation of water soluble 2′- and 7-taxol phosphates is reported. These derivatives were found to be poor prodrugs of taxol based on their marginal in vivo antitumor activity against ip,ip M109 murine tumor model and taxol release studies in vitro .

Pyrrolidine, pyrrolidinone, carbocyclic, and acyclic groups were used as isosteric proline replacements in a series of insulin-like growth factor I receptor kinase/insulin receptor kinase inhibitors. Examples that were similar in potency to proline-containing reference compounds were shown to project a key fluoropyridine amide into a common space, while less potent compounds were not able to do so for reasons of stereochemistry or structural rigidity.

The E-ring 4′-deshydroxy-4′-methyl analogs of the clinical antitumor agents etoposide and teniposide were synthesized from the corresponding 4′-triflates. These compounds display significant antitumor activity against murine P388 leukemia in vivo but are only 1/5 as cytotoxic against a human colon tumor cell line (HCT-116) grown in culture. These analogs also show inferior activity vis-a-vis etoposide and teniposide when evaluated for their ability to inhibit purified human topoisomerase II.

Reaction of etoposide ortho-quinone with primary amines results in products derived from transmination and reductive amination pathways. In contrast, thiols afford Michael adducts and/or thiol-quinone redox products.

The A ring of the clinical antitumor agent, etoposide, was opened to a protected 6,7-diphenol which was derivatized to form a number of new analogs. These compounds displayed activity inferior to etoposide when evaluated against several tumor cells line in vitro and against murine P388 leukemia in vivo .

The stereospecific synthesis of 6-α-hydroxy paclitaxel 10 , the major human metabolite of paclitaxel, is described. The 6,7-α-diol 4 , obtained from paclitaxel, is converted to the 6,7-β-cyclic sulfate followed by nitrate addition and reduction to afford the title compound.

The SAR of PXR transactivation by 3-(benzimidazol-2-yl)-pyridine-2-one based ATP competitive inhibitors of Insulin-like Growth Factor 1 Receptor kinase (IGF-1R) is discussed. Compounds without PXR transactivation, with in vivo antitumor activity, reduced protein binding and improved oral exposure are presented.

This report describes the biological activity, characterization, and SAR leading to 9d (BMS-754807) a small molecule IGF-1R kinase inhibitor in clinical development.

Publisher Summary This chapter focuses on the most recent advances in small molecule inhibitor design and specifically highlights those inhibitors that are entering the early stages of clinical development. The small molecule inhibitors of insulin-like growth factor-1receptor (IGF-1R) fall into two sub-categories: those that target the ATP-binding pocket of IGF-1R kinase (ATP-competitive) and those that target the substrate-binding site (non ATP-competitive). The most advanced small molecules are ATP-competitive kinase inhibitors. However, the greatest challenge for ATP-competitive inhibitors is achieving selectivity versus other kinases, including the closely related insulin receptor (IR) which shares high overall sequence homology and complete homology among the residues that contact ATP in the kinase-binding domain. In addition, it is interesting to follow the clinical development of molecules, such as AXL-1717, BMS-754807, INSM-18, OSI-906, and XL-228, with respect to efficacy, safety, and tolerability. The hope remains that small molecule inhibitors can provide a complementary approach to mAb therapeutics in terms of efficacy and dosing flexibility, particularly in combination studies with cytotoxics and epidermal growth factor receptor (EGFR) antagonists.

A series of cyclic acetal derivatives of mitomycin C (MC) and porfiromycin (POR) were tested for their ability to kill hypoxic and oxygenated EMT6 tumor cells. Amino methyl acetal and thioacetal substitutions at C-7 of MC and POR dramatically increased the cytotoxicity of the compounds to hypoxic EMT6 tumor cells in vitro but had little effect on the aerobic toxicities. In contrast, a methyl substitution at N1a markedly decreased the aerobic cytotoxicities of the compounds but did not alter the hypoxic cytotoxicities. The POR acetal, BMY-42355, had the largest differential between hypoxic and aerobic cytotoxicities yet observed among MC analogs. Preliminary studies in mice showed that BMY-42355 had good antineoplastic activity when used alone or in combination with radiation and was less toxic than POR; the therapeutic ratio of this compound in these initial studies was higher than those of either MC or POR.

A series of IGF-1R inhibitors is disclosed, wherein the (m-chlorophenyl)ethanol side chain of BMS-536924 (1) is replaced with a series of 2-(1H-imidazol-4-yl)ethanamine and 2-(1H-pyrazol-1-yl)ethanamine side chains. Some analogs show improved IGF-1R potency and oral exposure. Analogs from both series, 16a and 17f, show in vivo activity comparable to 1 in our constitutively activated IGF-1R Sal tumor model. This may be the due to the improved protein binding in human and mouse serum for imidazole 16a and the excellent oral exposure of pyrazole 17f.

The identification of a potent series of IKK-β selective inhibitors based on an imidazothienopyrazine template and the oral efficacy of one such analog (22j) in the LPS-induced TNF-α release mouse model are described.

Novel C-5 aminomethyl pyrrolotriazines were prepared and optimized for dual EGFR and HER2 protein tyrosine kinase inhibition. The homopiperazine, 1p, emerged as a key lead and it showed promising oral efficacy in EGFR and dual EGFR/HER2 driven human tumor xenograft models. It is hypothesized that the C-5 homopiperazine side chain binds in the ribose-phosphate portion of the ATP binding pocket.

A novel series of dual EGFR and HER2 inhibitors based on the pyrrolo[2,1-f][1,2,4]triazine nucleus is described. A general route toward their synthesis, which enables functionalization at multiple sites, has been developed. Biological evaluation in enzymatic and cell-based assays has identified a series of C-6 carbamates with potent biochemical and cellular activities.

[reaction: see text] Both 6'- and 4'-fluoro-glycosylated indolo[2,3-a]carbazoles are substrates for base-induced loss of fluorine as a leaving group from sp3 carbon. In the case of alpha-N-glycosylated substrate 3, loss of fluorine from the 6'-position leads to 3,6-anhydroglucose analogue 1. A novel N12,N13-bridged sugar analogue 2 results from loss of 4'-fluorine from beta-N-glycosylated analogue 4. Both analogues 1 and 2 display topo I inhibitory potencies similar to camptothecin.