(+)-4-[2-[4-(8-Chloro-3,10-dibromo-6,11-dihydro-5H-benzo[5, 6]cyclohepta[1,2-b]- pyridin-11(R)-yl)-1-piperidinyl]-2-oxo-ethyl]-1-piperidinecarboxamid e (SCH-66336): a very potent farnesyl protein transferase inhibitor as a novel antitumor agent.

We have previously shown that appropriate modification of the benzocycloheptapyridine tricyclic ring system can provide potent farnesyl protein transferase (FPT) inhibitors with good cellular activity. Our laboratories have also established that incorporation of either pyridinylacetyl N-oxide or 4-N-carboxamidopiperidinylacetyl moieties results in pharmacokinetically stable inhibitors that are orally efficacious in nude mice. We now demonstrate that further elaboration of the tricyclic ring system by introducing a bromine atom at the 7- or the 10-position of the 3-bromo-8-chlorotricyclic ring system provides compounds that have superior potency and selectivity in FPT inhibition. These compounds have good serum levels and half-lives when given orally to rodents and primates. In vitro and in vivo evaluation of a panel of these inhibitors has led to identification of 15 (SCH 66336) as a highly potent (IC50 = 1.9 nM) antitumor agent that is currently undergoing human clinical trials.

Identification of novel farnesyl protein transferase inhibitors using three-dimensional database searching methods.

Generation of a three-dimensional pharmacophore model (hypothesis) that correlates the biological activity of a series of farnesyl protein transferase (FPT) inhibitors, exemplified by the prototype 1-(4-pyridylacetyl)- 4-(8-chloro-5,6-dihydro-11H-benzo [5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine, Sch 44342, 1, with their chemical structure was accomplished using the three-dimensional quantitative structure-activity relationship (3D-QSAR) software program, Catalyst. On the basis of the in vitro FPT inhibitory activity of a training set of compounds, a five-feature hypothesis containing four hydrophobic and one hydrogen bond acceptor region was generated. Using this hypothesis as a three-dimensional query to search our corporate database identified 718 compounds (hits). Determination of the in vitro FPT inhibitory activity using available compounds from this "hitlist" identified five compounds, representing three structurally novel classes, that exhibited in vitro FPT inhibitory activity, IC50 < or = 5 microM. From these three classes, a series of substituted dihydrobenzothiophenes was selected for further structure-FPT inhibitory activity relationship studies. The results from these studies is discussed.

Structure-activity relationship of 3-substituted N-(pyridinylacetyl)-4- (8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene )- piperidine inhibitors of farnesyl-protein transferase: design and synthesis of in vivo active antitumor compounds.

Novel tricyclic Ras farnesyl-protein transferase (FPT) inhibitors are described. A comprehensive structure-activity relationship (SAR) study of compounds arising from substitution at the 3-position of the tricyclic pyridine ring system has been explored. In the case of halogens, the chloro, bromo, and iodo analogues 19, 22, and 28 were found to be equipotent. However, the fluoro analogue 17 was an order of magnitude less active. Whereas a small alkyl substituent such as a methyl group resulted in a very potent FPT inhibitor (SCH 56580), introduction of bulky substituents such as tert-butyl, compound 33, or a phenyl group, compound 29, resulted in inactive FPT inhibitors. Polar groups at the 3-position such as amino 5, alkylamino 6, and hydroxyl 12 were less active. Whereas compound SCH 44342 did not show appreciable in vivo antitumor activity, the 3-bromo-substituted pyridyl N-oxide amide analogue 38 was a potent FPT inhibitor that reduced tumor growth by 81% when administered q.i.d. at 50 mpk and 52% at 10 mpk. These compounds are nonpeptidic and do not contain sulfhydryl groups. They selectively inhibit FPT and not geranylgeranyl-protein transferase-1 (GGPT-1). They also inhibit H-Ras processing in COS monkey kidney cells and soft agar growth of Ras-transformed cells.

Isobenzofurans as conformationally constrained miconazole analogues with improved antifungal potency.

A series of halogen-substituted isobenzofuran analogues was synthesized, which represented conformationally constrained analogues of miconazole (1). In vitro and in vivo topical antifungal activity against both dermatophytes and Candida species varied widely, but 13c proved to be significantly superior to both 1 and clotrimazole against a vaginal Candida infection in hamsters, while 13b was significantly more active than 1 against a a topical Trichophyton infection in guinea pigs. None of the compounds were orally active. When the most direct analogue of 1 proved to be among the least active, a molecular modeling study was done using 1, the two active analogues 13b and 13c, and the inactive analogue 13a. All four compounds possessed skeletally similar conformations either at or energetically readily accessible from the global minimum energy conformations. This common conformation of the inactive analogue 13a, however, occupies unique molecular volume space associated with two chlorine atoms, which must also present unique electrostatic properties at the receptor. The conformation-activity relationships discussed may contribute toward deduction of additional structural requirements for pharmacophore optimization and more efficacious antifungal drugs.

Enzymatic modification of aminoglycoside antibiotics: a new 3-N-acetylating enzyme from a Pseudomonas aeruginosa isolate.

A new 3-N-aminoglycoside acetyltransferase is described, which possesses a wider substrate range than any such enzyme so far discovered in clinical isolates of antibiotic-resistant bacteria.