Anti-methanogenic lovastatin analogs or derivatives and uses thereof

Abstract

The present invention relates to, in part, methods for the treatment of methanogen-associated disorders such as, for example, Irritable Bowel Syndrome (IBS) using at least one anti-methanogenic lovastatin analog or derivative. In addition, modified-release formulations comprising at least one anti-methanogenic lovastatin analog or derivative are provided which release the anti-methanogenic lovastatin analog or derivative in the gastrointestinal tract.

1 . A method of inhibiting or reducing methanogenesis, or reducing or eliminating enteric methane production comprising administering an effective amount of an anti-methanogenic lovastatin analog or derivative to a subject in need thereof. 
     
     
         2 . The method of  claim 1 , wherein the subject suffers from irritable bowel syndrome. 
     
     
         3 . The method of any one of  claim 1 , wherein the subject suffers from constipation-associated IBS (IBS-C) and/or chronic idiopathic constipation (CIC). 
     
     
         4 . The method of  claim 1 , wherein the subject suffers from obesity. 
     
     
         5 . The method of  claim 1 , wherein the subject suffers from diabetes. 
     
     
         6 . (canceled) 
     
     
         7 . A method of treating constipation, constipation-associated IBS (IBS-C) and/or chronic idiopathic constipation (CIC), comprising administering an effective amount of an anti-methanogenic lovastatin analog or derivative to a subject in need thereof. 
     
     
         8 . The method of  claim 1 , wherein the anti-methanogenic lovastatin is a compound of one or more of the Formulae Ia-e, IIa-e, IIIa-e, IVa-e, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XVI, XVII, XVIII, XVIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV and XXXVI, as described herein. 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . The method of  claim 1 , wherein the anti-methanogenic lovastatin analog or derivative comprises one or more modifications relative to lovastatin in the lactone ring. 
     
     
         14 . The method of  claim 1 , wherein the anti-methanogenic lovastatin analog or derivative comprises one or more modifications relative to lovastatin that cause the anti-methanogenic lovastatin analog or derivative to be predominantly in the in the lactone form. 
     
     
         15 . The method of  claim 1 , wherein the anti-methanogenic lovastatin analog or derivative is predominantly in the lactone form in the subject's GI tract. 
     
     
         16 . The method of  claim 1 , wherein the anti-methanogenic lovastatin analog or derivative is not an effective inhibitor of HMG-CoA reductase. 
     
     
         17 . A modified-release formulation comprising at least one anti-methanogenic lovastatin analog or derivative, wherein the formulation releases at least 60% of the anti-methanogenic lovastatin analog or derivative after the stomach and into one or more regions of the intestinal tract. 
     
     
         18 . The modified-release formulation of  claim 17 , wherein the anti-methanogenic lovastatin is a compound of one or more of the Formulae Ia-e, IIa-e, IIIa-e, IVa-e, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XVI, XVII, XVIII, XVIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV and XXXVI, as described herein. 
     
     
         19 - 55 . (canceled) 
     
     
         56 . A method of inhibiting or reducing methanogenesis, comprising administering an effective amount of a formulation of  claim 17  to a subject in need thereof. 
     
     
         57 . The method of  claim 56 , wherein the subject suffers from irritable bowel syndrome. 
     
     
         58 - 68 . (canceled) 
     
     
         69 . The method of  claim 7 , wherein the anti-methanogenic lovastatin is a compound of one or more of the Formulae Ia-e, IIa-e, IIIa-e, IVa-e, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XVI, XVII, XVIII, XVIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV and XXXVI, as described herein. 
     
     
         70 . The formulation of any of  claim 17 , wherein the anti-methanogenic lovastatin analog or derivative is released in the small intestine. 
     
     
         71 . The formulation any of  claim 17 , wherein the anti-methanogenic lovastatin analog or derivative is released in the duodenum and/or jejunum. 
     
     
         72 . The formulation any of  claim 17 , wherein the anti-methanogenic lovastatin analog or derivative is released in the ileum and/or at the ileocecal junction.