H M G-CoA Reductase Inhibitors
`
`A. Endo and K. Hasumi
`Department of Applied Biological Science, Tokyo Noko University, Fuchu, Tokyo, 183 Japan
`
`Selectively reviewing the literature published up t o October 1992
`
`Introduction
`1
`Biochemical and Pharmacological Mechanisms
`2
`HMG-CoA Reductase
`2.1
`Plasma Cholesterol
`2.2
`Mevinic Acids of Fungal Origin
`3
`3.1
`Isolation
`Biosynthesis
`3.2
`Modification
`3.3
`4
`Synthetic Analogues
`5
`References
`
`1 Introduction
`Extensive epidemiological studies performed in many countries
`have shown that increased blood cholesterol levels, or, more
`specifically, increased levels of low density lipoprotein (LDL)
`cholesterol, are a major cause of coronary heart disease. There
`is also substantial evidence that lowering total and LDL
`cholesterol levels will reduce the incidence of coronary heart
`disease.l
`In 1976, Endo et al. reported the isolation of mevastatin
`(formerly called ML 236B or compactin) (1) as a potent
`inhibitor of hydroxymethylglutaryl coenzyme A (HMG-CoA)
`reductase, the rate-limiting enzyme in endogenous cholesterol
`synthesis.2. They elucidated biochemical mechanisms for the
`
`action of me~astatin~-~ and by 1980, had shown that mevastatin
`strikingly lowers total and LDL cholesterol in patients with
`hyperch~lesterolemia.~ These findings stimulated the world-
`wide development of mevastatin analogues in the 1980s and by
`1990, three drugs, lovastatin (formerly called mevinolinlO or
`monacolin K11,12) (2), simvastatin13 (3) and pravastatin14 (4),
`
`had been marketed in many c o ~ n t r i e s . ~ ~ , ~ ~ In addition to these,
`many other mevastatin analogues have been synthesized, some
`of which are now under clinical development.
`
`2 Biochemical and Pharmacological
`Mechanisms
`2.1 HMG-CoA Reductase
`HMG-CoA reductase, a 97 kDa glycoprotein," catalyses the
`reductive deacylation of HMG-CoA to mevalonate in a two-
`step reaction (Scheme 1).
`The stereospecificity of HMG-CoA reductase is illustrated in
`Scheme 1. Only the 3s isomer of HMG-CoA is utilized in the
`reaction.1s-20 Each hydride transfer involves the pro-R or 'A'
`side of the NADPH pyridine ring,21.22 the first forming the 3S,
`
`5R-thiohemiacetal, and the second incorporating the hydrogen
`into the 5-pro-S position of (3S)-me~alonate.~~.
`23. 24
`Mevastatin analogues are reversible competitive inhibitors of
`The K, value for mammalian HMG-
`HMG-CoA r e d ~ c t a s e . ~ ~ ' ~
`
`CoA reductase is - 10 ,UM, while the Ki value for the ring-
`
`opened acids of mevastatin (5) and lovastatin (6) are in the
`range of 0.2-1 n
`
`
`
` ~~.~Thus, the affinity of HMG-CoA reductase
`
`
`for mevastatin analogues is 10000-fold or more than its affinity
`for the natural substrate, HMG-CoA. The 3,5-dihydroxy-
`heptanoic acid portion of these compounds resembles the
`HMG portion of HMG-CoA (Scheme 1).
`The 3,5-dihydroxyheptanoic acid chain of mevastatin inter-
`acts with the HMG binding domain of the enzyme's active site.
`It has been postulated that the tight binding of mevastatin is the
`result of its ability to simultaneously interact with both the
`HMG binding domain and an adjacent hydrophobic pocket
`which is not utilized in substrate binding.26
`Kinetic studies have shown that the enzymatic reaction is
`consistent with the general chemical mechanism postulated for
`
`(1) R = H
`(2) R = Me
`
`(3)
`
`C02Na
`
`" ' Y O H
`
`0
`
`(4)
`
`(5) R = H
`(6) R = Me
`
`HO ,CH3
`
`CoA-S &02H
`
`3s-HMG-COA
`
`NADPH NADP+
`
`NADPH" NADP'
`
`3 S,5 R-Mevakfyl-CoA
`thiohemiacetal
`
`Scheme 1
`
`54 1
`
`3 R-Mevalonate
`
`38-2
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`
`542
`
`0 +&
`
`R'-
`
`ti I N
`
`"Do "vo "U0
`& & & &
`
`NATURAL PRODUCT REPORTS, 1993
`
`H 0 q C 0 2 H
`OH
`
`R'-
`
`(8) 0 0
`R = H
`
`R.*
`
`(9) R = 0 H
`
`,.-'
`
`(1 2) 0 ..*-
`
`\ (13) "OH
`
`(7) R = H
`(14) R = M e
`
`(10) R =Me
`
`(11) R = Me
`
`dehydrogenase catalysis in assisting direct transfer of a hydride
`ion between nucleotide and
`The pKa of this
`catalytic group is dependent on whether reduced or oxidized
`cofactor (NADPH or NADP', respectively) is bound at the
`active site. Mevastatin (1) apparently owes its inhibitory
`activity to the ability to mimic the half-reduced substrate
`mevalonate hemithioacetal. Therefore, by analogy, the 5-
`hydroxy group of mevastatin must interact with the un-
`protonated form of this catalytic group.
`Mevastatin analogues inhibit cholesterol biosynthesis in a
`variety of mammalian cell cultures at nM concentration^.^. 6 , 25
`In human skin fibroblast cultures, sterol synthesis from
`
`[14C]acetate is inhibited by 50% at - 1 nM. When mevastatin
`
`analogues are given orally to rats, sterol synthesis in the liver,
`the major organ of sterol synthesis, is acutely inhibited.,
`Mevastatin and lovastatin do not lower plasma cholesterol
`levels in rats and mice,28 but these agents are highly effective in
`reducing plasma cholesterol in dogs,29, 30
` rabbit^^^,^^
`and h ~ m a n s . ~ . ~ ~ * ~ ~ , ~ ~
`
`2.2 Plasma Cholesterol
`Cholesterol is transported in plasma in the form of lipoproteins.
`By means of ultracentrifugation six distinct classes of lipo-
`protein can be isolated from plasma. Most of the cholesterol in
`humans is carried by LDL.
`Mammalian cells from normal subjects possesses LDL
`receptors on the cell surface which bind LDL with a high-
`affinity.35 The bound LDL is incorporated into the cells and
`undergoes lysosomal digestion, leading to hydrolysis of
`cholesterol esters. The free cholesterol that is released serves to
`control the rate of cholesterol synthesis within the cells by
`down-regulating HMG-CoA reductase.l' The chief role of the
`LDL receptor is to provide a constantly available source of
`cholesterol throughout the body. Mutations of the gene
`encoding the LDL receptor results in impaired degradation of
`LDL and thus cause familial hypercholesterolemia (FH).36
`Endogenous cholesterol synthesis is decreased by exposing
`cells to LDL which facilitates delivery of exogenous cholesterol
`and thus down-regulates HMG-CoA r e d ~ c t a s e . ~ ~
`The co-ordinate regulation of LDL receptor expression and
`
`_.
`CH3CCOONa
`A
`CH3SCH2CH&H(NH*)COOH
`
`Scheme 2
`
`HMG-CoA reductase activity provides a homeostatic mech-
`anism for ensuring an adequate supply of cholesterol to cells
`such as hepatocytes which metabolize large amounts of LDL
`each day.36 HMG-CoA reductase inhibitors typified by
`mevastatin (1) block endogenous cholesterol synthesis, es-
`pecially in the liver which requires cholesterol as a substrate for
`bile acid synthesis4 To overcome the short-fall, hepatocytes
`express a greater number of LDL receptors and thereby
`
`promote influx of LDL cholesterol from ~ l a s m a . ~ ~ , ~ ' The net
`result is a decrease in plasma LDL cholesterol. Lovastatin (2)
`and simvastatin (3) are both lactones and inactive until
`metabolized in the liver to the open-ring hydroxy acids.
`
`3 Mevinic Acids of Fungal Origin
`3.1 Isolation
`Mevastatin (l), a metabolite of Penicillium citrinum, was
`isolated in 1973, filed for patent in 1974, and first described in
`the literature in 1976.2. This compound was independently
`isolated from P. brevicompactum as an antibiotic by Brown et
`al.38 Subsequently, lovastatin (2) was isolated from Monascus
`ruberll. l 2 and Aspergillus terreus,1° respectively. Lovastatin is
`slightly more potent than mevastatin in inhibiting HMG-CoA
`reductase. These compounds can be easily converted to the
`respective open-chain dihydroxy acids (5) and (6).
`Along with mevastatin, dihydrocompactin (7),39 ML-236A
`(S),2 and ML-236C (9)2 have been isolated from P. citrinum.
`Monacolin J
`monacolin L (1 l),,O dihydromonacolin L
`( l2),,l and 3a-hydroxy-3,5-dihydromonacolin L acid (1 3)42 are
`minor metabolites of M . ruber. Dihydromevinolin (14) is a
`product of A . t e r r e ~ s . , ~
`The class of compounds mentioned above, distinguished by
`a highly functionalized hexalin or octalin unit and a /3-hydroxy-
`6-lactone portion linked by an ethylene bridge, are collectively
`referred to as mevinic
`Dihydrocompactin (7) and dihydromevinolin (14) are com-
`parable to mevastatin and lovastatin, respectively, in inhibiting
`HMG-CoA reductase, while other metabolites that lack the
`side chain ester are far less active.25
`
`3.2 Biosynthesis
`[13C]Acetate, [methy1-l3C]methionine and 1802 are incorporated
`into mevastatin and lovastatin in cultures of P. citrinum, M .
`ruber and A . terreus, and the 'H and 13C NMR spectra of the
`two products have been fully assigned by a combination of
`spectral analyses. Both compounds are formed by the head-to-
`tail coupling of two polyketide chains (C, and C18) each derived
`from acetate units. The C, chain has one methionine derived
`methyl group, and a methyl group at C-6 in the bicyclic ring
`system of lovastatin is also derived from methionine (Scheme
`2).4547
`The above data suggest involvement of a biological Diels-
`Alder cyclization to generate the correct ring stereochemistry in
`a single step. Such ring forming processes have been suggested
`for a number of reduced polyketide metabolites.
`Mevinic acids isolated from M . ruber by Endo and co-
`workers include dihydromonacolin L (1 2), 3a-hydroxy-3,5-
`
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`NATURAL PRODUCT REPORTS, 1993-A. END0 AND K. HASUMI
`
`543
`
`Methionine
`
`(2)
`
`(10)
`
`(3)
`
`Reagents: i, LiOH, H,O, 100 "C; H,O+, toluene, 110°C; ii, TBSCl; iii, 2,2-dimethylbutyryl chloride; Bu"NF, HOAc
`Scheme 4
`
`Table 1 Effects of modification of the side chain ester moiety
`of lovastatin.
`
`R
`
`Relative potency"
`
`254
`
`K acid (6) can be derived from monacolin J acid (17) by M .
`r ~ b e r . ~ ~
`One possible mechanism for this conversion is the
`esterification of monacolin J acid with a-methylbutyryl-CoA to
`monacolin K acid. These results are summarized in Scheme 3.
`
`3.3 Modification
`The 2s-methylbutyryl ester of mevastatin and lovastatin, gave
`ML-236A and monacolin J, respectively, by hydrolysis with
`either alkali or carboxylesterase of the fungus Emericellu
`
`ur~guis.~O,~~ Hoffman et ul. at Merck, Sharp & Dohme (MSD)
`synthesized a series of the side chain ester analogues of
`lovastatin from monacolin J (Scheme 4).13 A systematic
`exploration of the structure-activity relationships showed that
`the introduction of an additional aliphatic group on the carbon
`01 to the carbonyl group increased potency (Table l).13 This
`observation led to the synthesis of simvastatin (3) (Scheme 4),
`which has about 2.5 times the intrinsic inhibitory activity of
`lovastatin (2).13 A process involving enolization/methylation
`of the 2s-methylbutyrate side chain of lovastatin also affords
`simvastatin highly effi~iently.~, Simvastatin has been marketed
`since 1988.
`Side chain ether analogues of lovastatin are weaker inhibitors
`of HMG-CoA reductase than the corresponding side chain
`ester analogues. Of the ether analogues prepared by Lee et al.,
`the 4-fluorobenzyl ether analogue (1 8) proved to enhance the
`potency.53
`
`" O U 0
`
`F
`
`A
`
`
`
`w
`a Potency of mevastatin is assigned a value of 100.
`
`15
`
`dihydromonacolin L acid (1 3), monacolin L (1 I), monacolin J
`(10) and monacolin K (lovastatin) (2). They have shown that
`dihydromonacolin L acid (1 5) is converted to 3a-hydroxy-3,5-
`dihydromonacolin L acid (13) by M . ruber in the presence of
`molecular oxygen.42 The
`latter can be spontaneously
`dehydrated to monacolin L acid (16), although conversion of
`exogenously added 301-hydroxy-3,5-dihydromonacolin L acid
`to monacolin L acid by M. ruber has not been successful.
`Monacolin L acid is hydroxylated to monacolin J acid (17) by
`the action of a mono~xygenase.~~ The end-product monacolin
`
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`544
`
`NATURAL PRODUCT REPORTS, 1993
`
`0
`
`0
`
`, O q r O
`
`(19) R = P-OH
`(20) R = a-OH
`
`(22) R = H
`(23) R =Me
`
`,
`
`(27) R' = CI, R2 = H
`(28) R'=H, R2=CI
`
`Modification of the hexahydronaphthalene ring 6-position in
`simvastatin (3) via oxygenation and oxa replacement by Duggan
`et al. led to the selection of (19) and (20) for pharmacological
`
`e v a l ~ a t i o n . ~ ~ These two compounds proved to be orally active
`as hypocholesterolemic agents in cholestyramine-primed dogs
`and also exhibit low peripheral plasma drug activity levels,
`which may minimize pharmacologically related side effects
`since the major site of cholesterol synthesis is the liver. (+)-6-
`Ethylmevastatin (21) is comparable to lovastatin in inhibitory
`PO tency . 55
`Pravastatin (4)14 is prepared by microbial transformati~n.~~.
`57
`The enzyme cytochrome P-450,,,
`is responsible for this
`conversion by Streptomyces carbophil~s.~~ Pravastatin is struc-
`turally different from lovastatin in that it contains a hydroxyl
`group in the hexahydronaphthalene ring, making pravastatin
`more hydrophilic than lovastatin. Pravastatin is comparable to
`mevastatin and lovastatin in inhibiting HMG-CoA reductase
`and in lowering plasma cholesterol. It has been on the market
`since 1989.
`The phosphorylated derivatives (22) and (23) are produced
`by the action of several fungal
`These derivatives are
`converted to the respective parent compounds ( 5 ) and (6) in the
`liver, when administered to rats.
`Compound L-669262 (24) is derived from simvastatin (3) by
`microbial conversion, and is 6-7
`times more active than
`simvastatin in inhibiting HMG-CoA reductase.60
`
`4 Synthetic Analogues
`Since the mid 1980s a plethora of work has been directed
`towards the preparation of synthetic analogues of mevastatin
`(1) and lovastatin (2) by many pharmaceutical companies. Of
`these studies, initial investigations at MSD served to delineate
`key structure-activity relationship for mevastatin-like mimics
`and afforded a series of moderately effective HMG-CoA
`reductase inhibitors bearing a monocyclic substituent, of which
`the ring-opened form of lactone (25) was the most potent.61.62
`In general, unless the hydroxy groups remain unsubstituted
`in an eryfhro relationship, inhibitory activity is greatly reduced.
`Furthermore, only one enantiomer of the ring-opened form of
`the lactone possesses the activity displayed by the racemate.61
`
`These findings reveal that the chiral lactone moiety is essential
`for biological activity.
`Insertion of a bridging unit other than ethyl or (E)-ethenyl
`between the Scarbin01 moiety and an appropriate lipophilic
`moiety (e.g. 2,4-dichlorphenyl) attenuates activity.61
`Further studies of a series of substituted derivatives of (25) at
`MSD provided a series of 7-[3,5-disubstituted( 1,l '-biphenyl)-2-
`yl]-3,5-dihydroxy-6-heptanoic acids, of which (26) possessed
`2.8 times the inhibitory activity of m e ~ a s t a t i n . ~ ~ X-ray
`crystallography studies on compound (26) showed it to possess
`the same chirality in the lactone ring as mevastatin. Potent
`inhibitory activity was not retained without concomitant sub-
`stitution at the 3- and 5-positions of the central phenyl ring of
`The type
`the biphenyl moiety with methyl or chloro
`and position of substituents on the external phenyl ring is
`critical. An electron-donating group (CH, or CH,O) in the 4'-
`position is detrimental, whereas a halogen (C1 or F) in this
`position is beneficial. Ring fusion of substituted biphenyls
`afforded products that were substantially less active, indicating
`that the dihedral angle between phenyl rings must be greater
`than 0" to maintain a high level of inhibitory potency.64
`Substituted naphthalene derivatives, (27) and (28), display
`about the same potency as m e ~ a s t a t i n . ~ ~
`Investigations at the Sandoz Research Institute further
`extended the findings obtained at MSD. The researchers chose
`indolyl derivatives by considering structures and molecular
`shapes of both coenzyme A and mevastatin. An extensive and
`rapid analogue program led to the choice of fluvastatin (XU62-
`320) (29) (Scheme 5) as a candidate for extensive biological
`testing.66 As compared to the respective sodium salts of
`mevastatin and lovastatin, fluvastatin is 22- and 10-fold more
`potent in inhibiting HMG-CoA reductase. However, fluvastatin
`is comparable to mevastatin in cholesterol-lowering activity in
`patients.67 This drug is now under development and expected to
`be marketed in 1993.
`Many synthetic analogues of mevastatin have been prepared
`at Hoechst AG. Baader et al. prepared compound (30), which
`is comparable to lovastatin with respect to inhibition of HMG-
`CoA reductase.68 However, the cholesterol-lowering activity of
`(30) in rabbits is slightly lower when compared to that of
`lovastatin. The same group prepared the pyridine analogue HR
`780 (31) (Scheme 6),69370 which exceeded the activity of
`
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`NATURAL PRODUCT REPORTS, 1993-A. END0 AND K. HASUMI
`
`+k
`F alp
`i -
`
`ii
`
`___L
`
`F
`
`F
`
`545
`
`iii
`
`__c
`
`CI
`
`I A
`
`F
`
`C02Na 2
`
`COOR
`
`v
`
`Reagents: i, EtOH, A, ii, ZnC1,; iii, Me,NCH=CHCHO, POCl,; NaOH; iv, NaH, Bu"Li; v, Et,B, THF; NaBH,, -78 "C; vi, MeOH, NaOH.
`Scheme 5
`
`(31)
`Reagents: i, Bu'Ph,SiCl; imidozole; ii, CH,CO,But, LDA; iii, Et,B, NaBH,; iv, MeC(OMe),H, H+; v, Bu,NF; vi, Swern oxidation; vii, base; viii,
`CF,CO,H
`
`Scheme 6
`
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`
`546
`
`NATURAL PRODUCT REPORTS, 1993
`
`" " ' C O H Hoqo
`
`C02Na
`
`C02Na
`H o q o
`I ONa
`
`F
`
`Fw
`'w
`
`R
`
`(33) R=Pr'
`(34) R = pCeH4F
`(35) R = S@-CeH4F)
`
`i
`(36)
`
`(37)
`
`(38)
`
`F
`
`\ /
`\ / - coNHQ
`
`(39)
`
`F
`
`(40) R = CI
`(41) R=OMe
`
`F
`
`F
`
`F
`
`v
`
`
`
`/ 0
`
`F
`
`t
`F
`
`F 6
`V -
`
`H3c0&wE'
`
`F
`
`.COOCH3
`
`H3C0
`
`vii
`f--
`
`viii
`
`N
`H
`
`vi c--
`
`H3c0*
`
`C02Na
`
`""-C,H
`
`(+)-Enantiomer
`(6)
`Reagents: i, neat, 180 "C; ii, CH,Cl,, DDQ; iii, THF, Red-Al; iv, THF, CH,I; v, THF, LiAlH,, reflux; CH2C12, PCC, rt; vi, THF,
`(EtO),POCH=CHNHCy, NaH, rt; vii, THF, pentan-2,4-dione, NaH, BuLi, 0 "C; THF, BEt,, NaBH,, -65 "C; viii, THF, S-( +>-
`phenylglycinol, 50 "C ; chromatography; ix, EtOH, NaOH, reflux.
`Scheme 7
`
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`A1
`NATURAL PRODUCT REPORTS, 1993-A. END0 AND K. HASU3
`
`547
`
`is several times higher than that of lovastatin analogues,
`enhancing the in vivo efficacy of the drug. Clinical trials with
`HR 780 are in progress.
`Compound (32), prepared by the investigators at Hoechst, is
`3-5 times more active than lovastatin in both in vitro and in vivo
`assays and is a promising candidate for development as a
`choles terol-lowering agent. The phenoxy- type inhibitors (3 3),
`(34) and (35) show more pronounced changes in their
`pharmacological
`These compounds are considerably
`stronger in vitro than lovastatin and highly efficacious in
`rabbits, whilst they have only moderate activity in dogs.
`Lovastatin exhibits comparable activity in these animal species.
`The analogues having 1 -N-methyltetrazol-5-y1 attached to
`the C-8 position of 9,9-bis(substituted aryl)-3,5-dihydroxy-6,8-
`nonadienoic acids have been prepared at Bristol-Meyers
`Squibb, of which BMY 22089 (36) is a promising candidate for
`
`d e ~ e l o p m e n t . ' ~ , ~ ~ The open chain salt form of the 4R,6S
`enantiomer of (36) inhibits HMG-CoA reductase with a K,
`value of 4.3 nM, a value comparable to that for lovastatin (2).75
`The hydroxyphosphinyl-containing inhibitor SQ 33 600 (37)
`is about as effective as pravastatin and lovastatin in inhibiting
`intravenous ad-
`de novo cholesterol biosynthesis on
`
`mini~tration.~~ SQ 33 600 also shows oral activity equivalent to
`that of pravastatin and lovastatin and is also effective as a
`hypocholesterolemic agent in rabbits, dogs and monkey^.'^ It
`has been chosen for clinical study in humans.
`A series of substituted pyridines containing a hydroxy-
`phosphinyl functionality have been prepared at Bristol-Meyers
`Squibb, leading to the synthesis of compound (38).77 Compound
`(38) exhibited acute in vivo activity in rats comparable to that
`of lovastatin and pravastatin.
`Investigators at
`the Warner-Lambert Company have
`
`reported a variety of substituted p y r r ~ l e , ~ ~ , ~ ~ quinoline,'O and
`pyrazolea1,82 mevalonolactones. Compound (39) is 5 times
`more potent
`than mevastatin
`
`in ~ i t r o . ~ ~ Two quinoline
`mevalonolactones, (40) and (4 l), are comparable to mevastatin
`both in vitro and in vivo.'O The optically active form of
`compound (42) is 5-10 times more potent than mevastatin both
`in vitro and in vivo.'2 Thus, the hypocholesterolemic activity of
`compound (42) in dogs was significant at doses of 0.1 mg/kg,
`while lovastatin did not show a statistically significant lowering
`at doses lower than 1 mg/kg.82
`Investigators at Rhone-Poulenc Rorer reported a series of
`mevastatin analogues containing a phenylcyclohexane group.
`Of these compounds, RG 12561 (dalvastatin) (43) was slightly
`more potent in inhibitory potency than 10vastatin.~~ RG 12561
`was evaluated in clinical trials for the treatment of hyper-
`cholesterolemia. The analogue (44) is 5 times more potent in
`vitro than l~vastatin.'~
`A research group at SmithKline Beecham reported alterna-
`tives to the 5-hydroxymethylene group of mevastatin analogues
`including a,a-difluoroketonesa4 and phosphinic
`Highly potent HMG-CoA reductase inhibitors have recently
`been discovered via synthetic variation of the substitution
`pattern of functionalized pyridines by investigators at Bayer
`AG. The 5-methoxymethyl derivative BAY W 6228 (45) is the
`most potent compound and has been selected for further
`development (Scheme 7).86 In the in vitro assay BAY W 6228 is
`110 times more potent than lovastatin. The absolute 3R,5S-
`stereochemistry in the 3,5-dihydroxy acid side chain is necessary
`for the inhibitory activity (Table 2). For optimal activity, a
`branched substituent, i.e. isopropyl, cycloakyl or aryl, at C-6 of
`the pyridine ring, in combination with an isopropyl (or
`cyclopropyl) group at C-2 and a p-fluorophenyl substituent at
`C-4, is required. Substitution at position 5 of the pyridine ring
`increased the potency, and the 5-methoxymethyl group of BAY
`W 6228 is essential for its outstanding in vitro and in vivo
`activity (Table 3).
`BAY W 6228 significantly reduces serum cholesterol levels in
`dogs at a daily dose of 30 ,ug/kg, and is thus at least 200 times
`more potent than lovastatin under the same condition^.'^ BAY
`W 6228 is under clinical development.
`
`Table 2 HMG-CoA reductase inhibitory activities of
`substituted pyridines (I). Stereochemistry of the side chain.
`F
`
`R
`OH OH
`&&COONa
`
`?H
`
`?H
`
`4-4-
`COONa
`
`x c
`
`,
`
`, a
`
`OH OH
`&Coma
`
`COON a
`
`Relative potency"
`
`110
`
`0.2
`
`0.2
`
`0.03
`
`40
`
`0.4
`
`a Potency of lovastatin is assigned a value of 1.
`
`lovastatin (2) in inhibiting sterol synthesis in HEP G2 cells. HR
`780 effectively lowers plasma cholesterol levels in normo-
`lipidemic and hyperlipidemic animals (rats, dogs and monkeys).
`Based on equipotent doses, the potency of HR 780 appears to
`be 5-10 times that of lovastatin. The plasma half-life of HR 780
`
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`
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`
`NCI Exhibit 2022
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`
`

`
`548
`
`NATURAL PRODUCT REPORTS, 1993
`
`Table 3 HMG-CoA reductase inhibitory activities of substituted pyridines (11).
`
`F
`
`COONa
`
`H3C0
`
`Substitution in position 5
`Relative
`R5
`potency"
`H
`0.8
`CH3
`12
`
`CH,OH
`
`CH,OCH,
`
`0"""
`2o Q,, 10
`0"""
`
`20
`20
`
`50
`
`3
`
`Substitution in positions 2 and 6
`Relative
`potencya
`< 0.01
`0.1
`
`R2
`CH3
`CH(CH,),
`
`R6
`CH3
`CH3
`
`CH(CH3)2 CH3
`
`CH(CH,), CH(CH3),
`
`CH(CH3)2
`
`CH(CH3)2
`
`CH(CH,), '0
`
`0.1
`
`50
`
`40
`
`2o
`
`1.6
`
`CH(CH,), '0 0.02
`
`CH(CH3)2
`
`l6
`
`Linker modifications
`
`A-B
`
`CH,-CH,
`
`CH=CH ( E )
`
`c=c
`
`Relative
`potency"
`
`0.7
`
`50
`
`20
`
`COOCH,
`
`30
`
`Substitution in position 4
`Relative
`potency"
`
`R4
`
`
`
`6
`
`Q
`
`Q
`F Q
`
`1
`
`50
`
`a Potency of lovastatin is assigned a value of 1.
`
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`Published on 01 January 1993. Downloaded by Reprints Desk on 19/05/2015 16:57:02.
`
`View Article Online
`
`NCI Exhibit 2022
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`
`

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