WordNet

mark or draw with a ruler; "rule the margins"
keep in check; "rule ones temper" (同)harness, rein
the duration of a monarchs or governments power; "during the rule of Elizabeth"
measuring stick consisting of a strip of wood or metal or plastic with a straight edge that is used for drawing straight lines and measuring lengths (同)ruler
(mathematics) a standard procedure for solving a class of mathematical problems; "he determined the upper bound with Descartes rule of signs"; "he gave us a general formula for attacking polynomials" (同)formula
(linguistics) a rule describing (or prescribing) a linguistic practice (同)linguistic rule
prescribed guide for conduct or action (同)prescript
a principle or condition that customarily governs behavior; "it was his rule to take a walk before breakfast"; "short haircuts were the regulation" (同)regulation
any one of a systematic body of regulations defining the way of life of members of a religious order; "the rule of St. Dominic"
directions that define the way a game or sport is to be conducted; "he knew the rules of chess"
decide with authority; "The King decreed that all firstborn males should be killed" (同)decree
decide on and make a declaration about; "find someone guilty" (同)find
have an affinity with; of signs of the zodiac
being one more than four (同)5, v
the cardinal number that is the sum of four and one (同)5, V, cinque, quint, quintet, fivesome, quintuplet, pentad, fin, Phoebe, Little Phoebe
a game resembling handball; played on a court with a front wall and two side walls

PrepTutorEJDIC

〈C〉『規則』,規定;法則 / 〈C〉『慣例』,慣習;通例,通則 / 〈U〉『支配』,統治;統治期間;統治権 / 〈C〉ものさし,定規(ruler) / 〈国・人など〉‘を'『支配する』,統治する,統御する / 《しばしば受動態で》〈感情などが〉〈人,人の行動など〉‘を'左右する,動かす / 〈裁判所・裁判官などが〉…‘と'裁決する,決定する / 〈紙〉‘に'線を引く / (…を)『支配する』,統治する《+『over』+『名』》 / (…について)裁決する,判定する《+『on』+『名』》;(…に反対の)裁決をする《+『against』+『名』(do『ing』)》・〈米俗〉抜群である、最高である
《所有・所属》…『の』,…のものである,…に属する・《材料・要素》…『でできた』,から成る・《部分》…『の』[『中の』] ・《数量・単位・種類を表す名詞に付いて》…の・《原因・動機》…『で』,のために(because of) ・《主格関係》…『の』,による,によって・《目的格関係》…『を』,の・《同格関係》…『という』・《関係・関連》…『についての』[『の』],の点で・《抽象名詞などと共に》…の[性質をもつ] ・《『It is』+『形』+『of』+『名』+『to』 doの形で,ofの後の名詞を意味上の主語として》・《分離》…『から』・《起原・出所》…『から』[『の』](out of) ・《『名』+『of』+『a』(『an』)+『名』の形で》…のような・《『名』+『of』+『mine』(『yours, his』など独立所有格)の形で》…の…・《時》(1)《副詞句を作って》…に《形容詞句を作って》…の・《時刻》《米》…前(to,《米》before)
〈C〉(数の)『5』;5の記号(5,Vなど) / 〈C〉5時,5分;5歳 / 〈U〉《複数扱い》5人,5個 / 〈C〉5人(5個)1組のもの / 〈C〉(カードの)5の札 / 『5の』,5個の;5人の / 《補語にのみ用いて》5歳の(で)
ファイブズ(三方を囲んだ壁に手またはバットでボールを打つゲーム)
支配する,統治する / 支配的な,優勢な,有力な / (法による)判決,決定

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/07/17 22:35:33」(JST)

wiki en

Lipinski's rule of five also known as the Pfizer's rule of five or simply the Rule of five (RO5) is a rule of thumb to evaluate druglikeness or determine if a chemical compound with a certain pharmacological or biological activity has properties that would make it a likely orally active drug in humans. The rule was formulated by Christopher A. Lipinski in 1997, based on the observation that most medication drugs are relatively small and lipophilic molecules.^[1]^[2]

The rule describes molecular properties important for a drug's pharmacokinetics in the human body, including their absorption, distribution, metabolism, and excretion ("ADME"). However, the rule does not predict if a compound is pharmacologically active.

The rule is important to keep in mind during drug discovery when a pharmacologically active lead structure is optimized step-wise to increase the activity and selectivity of the compound as well as to insure drug-like physicochemical properties are maintained as described by Lipinski's rule.^[3] Candidate drugs that conform to the RO5 tend to have lower attrition rates during clinical trials and hence have an increased chance of reaching the market.^[2]^[4]

Components of the rule[edit]

Lipinski's rule states that, in general, an orally active drug has no more than one violation of the following criteria:

Not more than 5 hydrogen bond donors (nitrogen or oxygen atoms with one or more hydrogen atoms)
Not more than 10 hydrogen bond acceptors (nitrogen or oxygen atoms)
A molecular mass less than 500 daltons
An octanol-water partition coefficient^[5] log P not greater than 5

Note that all numbers are multiples of five, which is the origin of the rule's name. As with many other rules of thumb, (such as Baldwin's rules for ring closure), there are many exceptions to Lipinski's Rule.

Variants[edit]

In an attempt to improve the predictions of druglikeness, the rules have spawned many extensions, for example the following:^[6]

Partition coefficient log P in −0.4 to +5.6 range
Molar refractivity from 40 to 130
Molecular weight from 180 to 500
Number of atoms from 20 to 70 (includes H-bond donors [e.g.;OH's and NH's] and H-bond acceptors [e.g.; N's and O's])
Polar surface area no greater than 140 Ǻ²

Also the 500 molecular weight cutoff has been questioned. Polar surface area and the number of rotatable bonds has been found to better discriminate between compounds that are orally active and those that are not for a large data set of compounds in the rat.^[7] In particular, compounds which meet only the two criteria of:

10 or fewer rotatable bonds and
polar surface area equal to or less than 140 Å²

are predicted to have good oral bioavailability.^[7]

Lead-like[edit]

During drug discovery, lipophilicity and molecular weight are often increased in order to improve the affinity and selectivity of the drug candidate. Hence it is often difficult to maintain drug-likeness (i.e., RO5 complicance) during hit and lead optimization. Hence it has been proposed that members of screening libraries from which hits are discovered should be biased toward lower molecular weight and lipophility so that medicinal chemists will have an easier time in delivering optimized drug development candidates that are also drug-like. Hence the rule of five has been extended to the rule of three (RO3) for defining lead-like compounds.^[8]

A rule of three compliant compound is defined as one that has:

octanol-water partition coefficient log P not greater than 3
molecular mass less than 300 daltons
not more than 3 hydrogen bond donors
not more than 3 hydrogen bond acceptors
not more than 3 rotatable bonds

References[edit]

^ Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (March 2001). "Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings". Adv. Drug Deliv. Rev. 46 (1-3): 3–26. doi:10.1016/S0169-409X(00)00129-0. PMID 11259830.
^ ^a ^b Lipinski CA (December 2004). "Lead- and drug-like compounds: the rule-of-five revolution". Drug Discovery Today: Technologies 1 (4): 337–341. doi:10.1016/j.ddtec.2004.11.007.
^ Oprea TI, Davis AM, Teague SJ, Leeson PD (2001). "Is there a difference between leads and drugs? A historical perspective". J Chem Inf Comput Sci 41 (5): 1308–15. doi:10.1021/ci010366a. PMID 11604031.
^ Leeson PD, Springthorpe B (November 2007). "The influence of drug-like concepts on decision-making in medicinal chemistry". Nat Rev Drug Discov 6 (11): 881–90. doi:10.1038/nrd2445. PMID 17971784.
^ Leo A, Hansch C, Elkins D (1971). "Partition coefficients and their uses". Chem Rev 71 (6): 525–616. doi:10.1021/cr60274a001.
^ Ghose AK, Viswanadhan VN, Wendoloski JJ (January 1999). "A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases". J Comb Chem 1 (1): 55–68. doi:10.1021/cc9800071. PMID 10746014.
^ ^a ^b Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD (June 2002). "Molecular properties that influence the oral bioavailability of drug candidates". J. Med. Chem. 45 (12): 2615–23. doi:10.1021/jm020017n. PMID 12036371.
^ Congreve M, Carr R, Murray C, Jhoti H (October 2003). "A 'rule of three' for fragment-based lead discovery?". Drug Discov. Today 8 (19): 876–7. PMID 14554012.

External links[edit]

Interactive Rule of Five calculator
Free online calculations of Hydrogen bond donor/acceptor, mass and logP using ChemAxon's Marvin and Calculator Plugins – requires Java
Calculation of Druglikeness – requires Java

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